Cortical modulations before lower limb motor blocks are associated with freezing of gait in Parkinson's disease: an EEG source localization study.

BACKGROUND: Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) characterized by paroxysmal episodes in which patients are unable to step forward. A research priority is identifying cortical changes before freezing in PD-FOG. METHODS: We tested 19 patients with PD who had been assessed for FOG (n=14 with FOG and 5 without FOG). While seated, patients stepped bilaterally on pedals to progress forward through a virtual hallway while 64-channel EEG was recorded. We assessed cortical activities before and during lower limb motor blocks (LLMB), defined as a break in rhythmic pedaling, and stops, defined as movement cessation following an auditory stop cue. This task was selected because LLMB correlates with FOG severity in PD and allows recording of high-quality EEG. Patients were tested after overnight withdrawal from dopaminergic medications ("off" state) and in the "on" medications state. EEG source activities were evaluated using individual MRI and standardized low resolution brain electromagnetic tomography (sLORETA). Functional connectivity was evaluated by phase lag index between seeds and pre-defined cortical regions of interest. RESULTS: EEG source activities for LLMB vs. cued stops localized to right posterior parietal area (Brodmann area 39), lateral premotor area (Brodmann area 6), and inferior frontal gyrus (Brodmann area 47). In these areas, PD-FOG (n=14) increased alpha rhythms (8-12 Hz) before LLMB vs. typical stepping, whereas PD without FOG (n=5) decreased alpha power. Alpha rhythms were linearly correlated with LLMB severity, and the relationship became an inverted U-shape when assessing alpha rhythms as a function of percent time in LLMB in the "off" medication state. Right inferior frontal gyrus and supplementary motor area connectivity was observed before LLMB in the beta band (13-30 Hz). This same pattern of connectivity was seen before stops. Dopaminergic medication improved FOG and led to less alpha synchronization and increased functional connections between frontal and parietal areas. CONCLUSIONS: Right inferior parietofrontal structures are implicated in PD-FOG. The predominant changes were in the alpha rhythm, which increased before LLMB and with LLMB severity. Similar connectivity was observed for LLMB and stops between the right inferior frontal gyrus and supplementary motor area, suggesting that FOG may be a form of "unintended stopping." These findings may inform approaches to neurorehabilitation of PD-FOG.

Interhemispheric interactions between the right angular gyrus and the left motor cortex: a transcranial magnetic stimulation study.

The interconnection of the angular gyrus of right posterior parietal cortex (PPC) and the left motor cortex (LM1) is essential for goal-directed hand movements. Previous work with transcranial magnetic stimulation (TMS) showed that right PPC stimulation increases LM1 excitability, but right PPC followed by left PPC-LM1 stimulation (LPPC-LM1) inhibits LM1 corticospinal output compared with LPPC-LM1 alone. It is not clear if right PPC-mediated inhibition of LPPC-LM1 is due to inhibition of left PPC or to combined effects of right and left PPC stimulation on LM1 excitability. We used paired-pulse TMS to study the extent to which combined right and left PPC stimulation, targeting the angular gyri, influences LM1 excitability. We tested 16 healthy subjects in five paired-pulsed TMS experiments using MRI-guided neuronavigation to target the angular gyri within PPC. We tested the effects of different right angular gyrus (RAG) and LM1 stimulation intensities on the influence of RAG on LM1 and on influence of left angular gyrus (LAG) on LM1 (LAG-LM1). We then tested the effects of RAG and LAG stimulation on LM1 short-interval intracortical facilitation (SICF), short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI). The results revealed that RAG facilitated LM1, inhibited SICF, and inhibited LAG-LM1. Combined RAG-LAG stimulation did not affect SICI but increased LICI. These experiments suggest that RAG-mediated inhibition of LAG-LM1 is related to inhibition of early indirect (I)-wave activity and enhancement of GABAB receptor-mediated inhibition in LM1. The influence of RAG on LM1 likely involves ipsilateral connections from LAG to LM1 and heterotopic connections from RAG to LM1.NEW & NOTEWORTHY Goal-directed hand movements rely on the right and left angular gyri (RAG and LAG) and motor cortex (M1), yet how these brain areas functionally interact is unclear. Here, we show that RAG stimulation facilitated right hand motor output from the left M1 but inhibited indirect (I)-waves in M1. Combined RAG and LAG stimulation increased GABAB, but not GABAA, receptor-mediated inhibition in left M1. These findings highlight unique brain interactions between the RAG and left M1.

EEG oscillations: how are they modulated during different phases of repetitive movements?

Voluntary movements are planned through the relative timing between submovements of movement sequences as part of the motor program. Different movement phases are characterized by specific amplitude modulation of cortical oscillations. The latter represent neurophysiological correlates of specific synchronization or desynchronization of different neuronal groups. In this Neuro Forum, we review recent evidence regarding the temporal relation between neurophysiological correlates of different phases of a repetitive motor task using electroencephalography and source localization using individualized MRI.

Differential effects of continuous theta burst stimulation over left premotor cortex and right prefrontal cortex on modulating upper limb somatosensory input.

Somatosensory evoked potentials (SEPs) represent somatosensory processing in non-primary motor areas (i.e. frontal N30 and N60) and somatosensory cortices (i.e. parietal P50). It is well-known that the premotor cortex (PMC) and prefrontal cortex (PFC) are involved in the preparation and planning of upper limb movements but it is currently unclear how they modulate somatosensory processing for upper limb motor control. In the current study, two experiments examined SEP modulations after continuous theta burst stimulation (cTBS) was used to transiently disrupt the left PMC (Experiment 1) and right PFC (Experiment 2). Both Experiment 1 (n=15) and Experiment 2 (n=16) used pre-post experimental designs. In both experiments participants performed a task requiring detection of varying amplitudes of attended vibrotactile (VibT) stimuli to the left index finger (D2) and execution of a pre-matched finger sequence with the right (contralateral) hand to specific VibT targets. During the task, SEPs were measured to median nerve (MN) stimulations time-locked during pre-stimulus (250 ms before VibT), early response selection (250 ms after VibT), late preparatory (750 ms after VibT) and execution (1250 ms VibT) phases. The key findings of Experiment 1 revealed significant decreases in N30 and N60 peak amplitudes after cTBS to PMC. In contrast, the results of Experiment 2, also found significant decreased N60 peak amplitudes as well as trends for increased N30 and P50 peak amplitudes. A direct comparison of Experiment 1 and Experiment 2 confirmed differential modulation of N30 peak amplitudes after PMC (gated) compared to PFC (enhanced) cTBS. Collectively, these results support that both the left PMC and right PFC have modulatory roles on early somatosensory input into non-primary motor areas, such as PMC and supplementary motor area (SMA), represented by frontal N30 and N60 SEPs. These results confirm that PMC and PFC are both part of a network that regulates somatosensory input for upper limb motor control.

Modulatory effects of movement sequence preparation and covert spatial attention on early somatosensory input to non-primary motor areas.

Early frontal somatosensory evoked potentials (SEPs) (i.e., N30) are known to be modulated by movement. Furthermore, individuals with prefrontal lesions have enhanced early frontal SEPs. However, it is currently unclear through what mechanism the prefrontal cortex may modulate early frontal SEPs. The current study investigated whether prefrontal modulatory effects on frontal SEPs may depend on the relevancy of somatosensory input for movement (i.e., interaction with motor areas). Two experiments were conducted to determine whether selective spatial attention alone (Experiment 1-Attend and Mentally Count) or when using attended somatosensory input in the preparation of finger sequences with the limb contralateral to somatosensory stimulation (Experiment 2-Attend for Movement Preparation) could modulate SEPs. In Experiment 1, SEPs elicited by median nerve (MN) stimulation at both wrists were measured in trials when individuals attended and mentally counted vibrotactile (VibT) input at either index finger. In Experiment 2, SEPs elicited by MN stimulation at the left wrist were measured in trials when individuals used attended VibT input at the left index finger to prepare finger sequences that were contralateral to MN stimulation. In both experiments, control conditions were performed where participants received passive VibT and MN stimulation. Results from Experiment 1 confirmed that selective spatial attention alone does not modulate frontal N30 peak amplitudes. However, Experiment 2 revealed that frontal N30 peak amplitudes were decreased (i.e., gated) when individuals used attended VibT input at the left index finger to prepare contralateral finger sequences. These results support a role of sensory gating of early frontal SEPs during finger sequence preparation of the limb contralateral to MN stimulation that may result from increased activity in prefrontal, motor preparatory areas, and basal ganglia.

Longitudinal evaluations of somatosensory-motor inhibition in Dopa-responsive dystonia.

INTRODUCTION: GCH1 mutations have been linked to decreased striatal dopamine and development of dopa-responsive dystonia (DRD) and Parkinsonism. Sensory and sensorimotor integration impairments have been documented in various forms of dystonia. DRD patients with confirmed GCH1 mutations have demonstrated normal short-latency afferent inhibition (SAI), a measure of sensorimotor inhibition, under chronic dopaminergic replacement therapy (DRT), but reduced inhibition after a single l-dopa dose following 24 h withdrawal. Studies have revealed normal SAI in other forms of dystonia but reductions with DRT in Parkinson's disease. Longitudinal changes in sensorimotor inhibition are unknown. METHODS: We analyzed sensorimotor inhibition using two different measures: SAI and somatosensory-motor inhibition using dual-site transcranial magnetic stimulation (ds-TMS). SAI was measured using digit stimulation 25 ms prior to contralateral primary motor cortex (M1) TMS. DS-TMS was measured using TMS over the somatosensory cortex 1 or 2.5 ms prior to ipsilateral M1 stimulation. A total of 20 GCH1 mutation carriers and 20 age-matched controls were included in the study. SAI and ds-TMS were evaluated in GCH1 mutation carriers both OFF and ON DRT compared to controls. Furthermore, longitudinal changes of SAI were examined in a subset of the same individuals that were measured âˆ¼five years earlier. RESULTS: Neither SAI nor ds-TMS were significantly different in GCH1 mutation carriers relative to controls. No effects of DRT on SAI or ds-TMS were seen but SAI decreased over time in mutation carriers OFF DRT. CONCLUSION: Our longitudinal results suggest changes in SAI that could be associated with plasticity changes in sensorimotor networks.

Evaluating dopaminergic system contributions to cued pattern switching during bimanual coordination.

Switching between different coordinated movements has been shown to be slow, with delayed responses and even freezing deficits in individuals with Parkinson's disease (PD). While it is well accepted that the dopaminergic system responds to dopamine replacement to ameliorate overall slowness (bradykinesia) and other motor symptoms of PD, it is unknown whether the dopaminergic system can influence overall coordination between limbs and if this may be impacted by the availability of sensory feedback. In the current study, PD and healthy age-matched control participants performed a rhythmic coordination task that required a cued voluntary switch between movement patterns (in-phase and anti-phase). PD participants performed the task first after overnight withdrawal ('off'), and subsequently after administration ('on') of dopamine replacement. Coordinated movements were performed while paced by an auditory metronome in two sensory conditions: 'no vision' or 'normal vision'. Measures of voluntary switch time and delayed responses revealed that PD 'off' required significantly more time than healthy participants to switch between movement patterns. Interestingly, PD 'off' demonstrated disrupted coordination, as revealed by mean (accuracy) and standard deviation (stability) of absolute error of relative phase. Dopamine replacement improved the time needed to switch and amount of delayed responses in PD participants, but had no influence on coordination itself. It is concluded that although modulation of the dopaminergic system improves the slowness during switching, coordination deficits may be the result of secondary impairments (possibly attention-related) that cannot be improved with dopamine replacement.

Motor blocks during bilateral stepping in Parkinson's disease and effects of dopaminergic medication.

INTRODUCTION: Freezing of gait (FOG) is a complex symptom in Parkinson's disease (PD) that manifests during walking as limited forward progression despite the intention to walk. It is unclear if lower limb motor blocks (LLMB) that occur independently from FOG are related to overground FOG and the effects of dopaminergic medications. METHODS: Nineteen patients with PD were tested on two separate days in the dopaminergic medication "on" and "off" states. The patients completed a series of freezing-provoking tasks while videotaped. Raters assessed videos for FOG presence using Movement Disorders Society Unified Parkinson's Disease Rating Scale item 3.11 score greater than or equal to 1 and FOG severity using the standardized FOG score. Whilst seated in a virtual environment, patients and 20 healthy controls stepped in right-left sequence on foot pedals. Frequency and percent time in LLMB were assessed for accurate classification of FOG presence and correlation to the FOG score. RESULTS: Frequency and percent time spent in LLMB predicted the presence of FOG in both medication states. Percent time spent in LLMB correlated with FOG severity in both medication states. LLMB frequency predicted FOG severity in the "off" state only. CONCLUSIONS: LLMB during bilateral stepping in a virtual environment predicted the presence and severity of FOG in PD in both "on" and "off" medication states. These findings support the use of this non-walking paradigm to detect and assess FOG in PD patients unable or unsafe to walk.

Reversal of Visual Feedback Modulates Somatosensory Plasticity.

Reversed visual feedback during unimanual training increases transfer of skills to the opposite untrained hand and modulates plasticity in motor areas of the brain. However, it is unclear if unimanual training with reversed visual feedback also affects somatosensory areas. Here we manipulated visual input during unimanual training using left-right optical reversing spectacles and tested whether unimanual training with reversed vision modulates somatosensory cortical excitability to facilitate motor performance. Thirty participants practiced a unimanual ball-rotation task using the right hand with either left-right reversed vision (incongruent visual and somatosensory feedback) or direct vision (congruent feedback) of the moving hand. We estimated cortical excitability in primary somatosensory cortex (S1) before and after unimanual training by measuring somatosensory evoked potentials (SEPs). This was done by electrically stimulating the median nerve in the wrist while participants rested, and recording potentials over both hemispheres using electroencephalography. Performance of the ball-rotation task improved for both the right (trained) and left (untrained) hand after training across both direct and reversed vision conditions. Participants with direct vision of the right hand during training showed SEPs amplitudes increased bilaterally. In contrast, participants in the reversed visual condition showed attenuated SEPs following training. The results suggest that cortical suppression of S1 activity supports skilled motor performance after unimanual training with reversed vision, presumably by sensory gating of afferent signals from the movement. This finding provides insight into the mechanisms by which visual input interacts with the sensorimotor system and induces neuroplastic changes in S1 to support skilled motor performance.

Using Dual-Site Transcranial Magnetic Stimulation to Probe Connectivity between the Dorsolateral Prefrontal Cortex and Ipsilateral Primary Motor Cortex in Humans.

Dual-site transcranial magnetic stimulation to the primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) can be used to probe functional connectivity between these regions. The purpose of this study was to characterize the effect of DLPFC stimulation on ipsilateral M1 excitability while participants were at rest and contracting the left- and right-hand first dorsal interosseous muscle. Twelve participants were tested in two separate sessions at varying inter-stimulus intervals (ISI: 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, and 20 ms) at two different conditioning stimulus intensities (80% and 120% of resting motor threshold). No significant effect on ipsilateral M1 excitability was found when applying a conditioning stimulus over DLPFC at any specific inter-stimulus interval or intensity in either the left or right hemisphere. Our findings suggest neither causal inhibitory nor faciliatory influences of DLPFC on ipsilateral M1 activity while participants were at rest or when performing an isometric contraction in the target hand muscle.

Somatosensory-motor cortex interactions measured using dual-site transcranial magnetic stimulation.

BACKGROUND: Dual-site transcranial magnetic stimulation (ds-TMS) is a neurophysiological technique to measure functional connectivity between cortical areas. OBJECTIVE/HYPOTHESIS: To date, no study has used ds-TMS to investigate short intra-hemispheric interactions between the somatosensory areas and primary motor cortex (M1). METHODS: We examined somatosensory-M1 interactions in the left hemisphere in six experiments using ds-TMS. In Experiment 1 (n = 16), the effects of different conditioning stimulus (CS) intensities on somatosensory-M1 interactions were measured with 1 and 2.5 ms inter-stimulus intervals (ISIs). In Experiment 2 (n = 16), the time-course of somatosensoy-M1 interactions was studied using supra-threshold CS intensity at 6 different ISIs. In Experiment 3 (n = 16), the time-course of short-interval cortical inhibition (SICI) and effects of different CS intensities on SICI were measured similar to Experiments 1 and 2. Experiment 4 (n = 13) examined the effects of active contraction on SICI and somatosensory-M1 inhibition. Experiments 5 and 6 (n = 10) examined the interactions between SAI with either 1 ms SICI or somatosensory-M1 inhibition. RESULTS: Experiments 1 and 2 revealed reduced MEP amplitudes when applying somatosensory CS 1 ms prior to M1 TS with 140 and 160% CS intensities. Experiment 3 demonstrated that SICI at 1 and 2.5 ms did not correlate with somatosensory-M1 inhibition. Experiment 4 found that SICI but not somatosensory-M1 inhibition was abolished with active contraction. The results of Experiments 5-6 showed SAI was disinhibited in presence of somatosensory-M1 while SAI was increased in presence of SICI. CONCLUSION: Collectively, the results support the notion that the somatosensory areas inhibit the ipsilateral M1 at very short latencies.

Neurophysiological Changes Measured Using Somatosensory Evoked Potentials.

Measurements of somatosensory evoked potentials (SEPs), recorded using electroencephalography during different phases of movement, have been fundamental in understanding the neurophysiological changes related to motor control. SEP recordings have also been used to investigate adaptive plasticity changes in somatosensory processing related to active and observational motor learning tasks. Combining noninvasive brain stimulation with SEP recordings and intracranial SEP depth recordings, including recordings from deep brain stimulation electrodes, has been critical in identifying neural areas involved in specific temporal stages of somatosensory processing. Consequently, this fundamental information has furthered our understanding of the maladaptive plasticity changes related to pathophysiology of diseases characterized by abnormal movements, such as Parkinson's disease, dystonia, and functional movement disorders.

Cerebellar involvement in Parkinson's disease resting tremor.

BACKGROUND: There exists a lack of consensus regarding how cerebellar over-activity might influence tremor in Parkinson's disease (PD). Specifically, it is unclear whether resting or postural tremor are differentially affected by cerebellar dysfunction. It is important to note that previous studies have only evaluated the influence of inhibitory stimulation on the lateral cerebellum, and have not considered the medial cerebellum. The aim of the current study was to compare the effects of a low-frequency rTMS protocol applied to the medial versus lateral cerebellum to localize the effects of cerebellar over-activity. METHODS: Fifty PD participants were randomly assigned to receive stimulation over the medial cerebellum (n = 20), lateral cerebellum (n = 20) or sham stimulation (n = 10). 900 pulses were delivered at 1Hz at 120 % resting motor threshold of the first dorsal interosseous muscle. Tremor was assessed quantitatively (before and after stimulation) using the Kinesia Homeview system which utilizes a wireless finger accelerometer to record tremor. RESULTS: The main finding was that resting tremor severity was reduced in tremor-dominant individuals, regardless of whether stimulation was applied over the medial (p = 0.024) or lateral (p = 0.033) cerebellum, but not in the sham group. CONCLUSION: Given that the cerebellum is overactive in PD, the improvements in resting tremor following an inhibitory stimulation protocol suggest that over-activity in cerebellar nuclei may be involved in the generation of resting tremor in PD. Low-frequency rTMS over the medial or lateral cerebellum provides promise of an alternative treatment for tremor in PD, a symptom that is poorly responsive to dopaminergic replacement.

Somatosensory input to non-primary motor areas is enhanced during preparation of cued contraterlateral finger sequence movements.

Frontal N30 somatosensory evoked potentials (SEPs) represent early somatosensory input into non-primary motor areas. Importantly, modulations of frontal N30 SEPs can provide insight into the mechanisms involved in sensory processing for movement control. Enhancements of frontal N30 SEPs have been revealed during repetitive but not during the preparation of movements that are contralateral to median nerve (MN) stimulation (i.e. contralateral movements). Importantly, these enhancements during contralateral movements may be dependent on increased activity in several neural areas such as the primary motor cortex (M1), supplementary motor area (SMA) and basal ganglia (BG). Furthermore, research has also shown that patients with prefrontal lesions have enhanced early frontal SEPs (i.e. N28) at rest supporting a role of the prefrontal cortex in inhibitory modulation of early somatosensory input. The current study evaluated whether differential modulations of frontal N30 SEPs occurred during different time periods when individuals prepared and executed contralateral (right) finger sequences to attended vibrotactile (VibT) stimuli at the left index finger. SEPs were measured to median nerve (MN) stimuli elicited at the left wrist and MN stimuli were time-locked in four different periods relative to VibT onset (during pre-stimulus, early response preparation, late movement preparation and movement execution). Results revealed that frontal N30 SEPs were significantly enhanced when MN stimulation occurred in the late preparatory and/or early movement execution period (∼750 ms) after the attended VibT stimuli. This result supports that increases in frontal N30 amplitudes during contralateral movements are dependent on the complexity of preparing and executing finger sequences, which is associated with increased activity in several neural areas such as the non-primary motor areas, prefrontal cortex and BG. Furthermore, enhanced N30 SEPs during contralateral movement preparation and execution may be a necessary mechanism to decrease sensory gating to facilitate somatosensory processing in non-primary motor areas when there is a 'noisy' environment.

The dopaminergic system in upper limb motor blocks (ULMB) investigated during bimanual coordination in Parkinson's disease (PD).

Upper limb motor blocks (ULMB) (inability to initiate or sudden discontinue in voluntary movements) have been identified in both unimanual and bimanual tasks in individuals with Parkinson's disease (PD). In particular, ULMB have been observed during rhythmic bimanual coordination when switching between phase patterns which is required (e.g. between in-phase and anti-phase). While sensory-perceptual mechanisms have recently been suggested to be involved in lower limb freezing, there has been no consensus on the mechanism that evokes ULMB or whether motor blocks respond to dopamine replacement like other motor symptoms of PD. The current study investigated the occurrence of ULMB in PD participants without ('off') and with ('on') dopamine replacement using bimanual wrist flexion-extension with external auditory cues. In Experiment 1, coordination was performed in either in-phase (simultaneous flexion and extension) or anti-phase (asymmetrical flexion and extension between the limbs) in one of three sensory conditions: no vision, normal vision or augmented vision. Cycle frequency was increased within each trial across seven cycle frequencies (0.75-2 Hz). In Experiment 2, coordination was initiated in either phase pattern and participants were cued to make an intentional switch between phases in the middle of trials. Trials were performed at one of two cycle frequencies (1 or 2 Hz) and one of two sensory conditions: no vision or normal vision. Healthy age-matched control participants were also investigated in both experiments for the occurrence of motor blocks that were measured using automated detection from a computer algorithm. The results from Experiment 1 indicated that increasing cycle frequency resulted in more ULMB in individuals with PD during continuous coordinated movement, regardless of dopaminergic status, phase pattern or sensory condition. Experiment 2 also confirmed an increased occurrence of ULMB with increased cycle frequency. Furthermore, a large amount of ULMB were observed when initiating anti-phase coordination at 2 Hz, as well as after both externally-cued switches and in 'catch trials' with distracting auditory cues when no switch was required. Dopamine replacement was not found to influence the frequency of ULMB in either experiment. Therefore, ULMB likely result from non-hypodopaminergic impairments associated with PD. Specifically, ULMB may be caused by an inability to shift attentional control under increased cognitive demand that could be associated with hypoactivation in motor and prefrontal areas.