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.

Subthalamic nucleus conditioning reduces premotor-motor interaction in Parkinson's disease.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus is effective to alleviate motor symptoms in advanced Parkinson's disease. Using a novel conditioning paradigm, it has been shown that deep brain stimulation pulses from electrodes in the subthalamic nucleus modulate corticospinal excitability as determined with transcranial magnetic stimulation applied to the motor cortex. The mechanism of action is unclear. OBJECTIVE: To investigate the effects of subthalamic nucleus and dorsal premotor cortex conditioning on corticospinal excitability as a function of interstimulus intervals between target areas and deep brain stimulation frequencies. METHODS: In 19 patients with Parkinson's disease with subthalamic nucleus deep brain stimulation, the premotor-motor interaction was investigated in four different deep brain stimulation conditions (off, clinically used settings, 3 Hz, 20 Hz). Transcranial magnetic pulses were applied to the premotor and motor cortex and paired at certain intervals with deep brain stimulation pulses. The volume of tissue activated by deep brain stimulation was correlated with neurophysiological findings. RESULTS: There was distinct motor cortex inhibition by premotor cortex conditioning at an interstimulus interval of 1 ms before the motor cortex stimulation. Subthalamic nucleus conditioning with deep brain stimulation frequencies of 3 and 20 Hz at an interstimulus interval of 10 ms between subthalamic nucleus and primary motor cortex reduced premotor-motor inhibition. The volume of tissue activated by deep brain stimulation correlated positively with this effect. Corticospinal excitability was not affected by subthalamic nucleus conditioning as used here. CONCLUSIONS: Premotor-motor inhibition is modulated by subthalamic nucleus conditioning, presumably through the monosynaptic hyperdirect pathway.

Impaired motor cortical facilitatory-inhibitory circuit interaction in Parkinson's disease.

OBJECTIVE: Motor cortical (M1) inhibition and facilitation can be studied with short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF). These circuits are altered in Parkinson's disease (PD). The sensorimotor measure short latency afferent inhibition (SAI) is possibly altered in PD. The aim was to determine if the manner in which these circuits interact with each other is abnormal in PD. METHODS: Fifteen PD patients were studied at rest in ON and OFF medication states, and were compared to 16 age-matched controls. A triple-stimulus transcranial magnetic stimulation paradigm was used to elicit a circuit of interest in the presence of another circuit. RESULTS: SICF was increased in PD OFF and PD ON conditions compared to controls. SICI facilitated SICF in controls and PD ON, but not in PD OFF. SICF in the presence of SICI negatively correlated with UPDRS-III scores in OFF and ON medication conditions. SAI showed similar inhibition of SICI in controls, PD OFF and PD ON conditions. CONCLUSIONS: The facilitatory effect of SICI on SICF is absent in PD OFF, but is restored with dopaminergic medication. SIGNIFICANCE: Impaired interaction between M1 circuits is a pathophysiological feature of PD.

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.

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.

A Distinct EEG Marker of Celiac Disease-Related Cortical Myoclonus.

BACKGROUND: Celiac disease is associated with motor cortex hyperexcitability and neurological manifestations including cortical myoclonus. Electroencephalography abnormalities have been described, but no distinct pattern has been reported. METHODS: We describe the neurophysiological characteristics of 3 patients with celiac-associated cortical myoclonus using electroencephalography, magnetoencephalography, and transcranial magnetic stimulation. RESULTS: Electroencephalography in all cases demonstrated lateralized low-amplitude, electropositive beta-frequency polyspike activity over the central head region, corresponding to motor cortex contralateral to the myoclonic limb. Jerk-locked back-averaging demonstrated a preceding cortical potential; magnetoencephalography source localization revealed a cortical generator in the posterior wall of the precentral gyrus for the back-averaged potential and oscillatory abnormality. In 1 patient, cerebellar inhibition of the motor cortex was physiologically normal. CONCLUSIONS: Central head oscillatory, low-amplitude, electropositive electroencephalography polyspike activity may be a distinct marker of celiac-related cortical myoclonus and is consistent with celiac-related motor cortex hyperexcitability, which may not necessarily result from cerebellar disinhibition. © 2020 International Parkinson and Movement Disorder Society.

Single-pulse subthalamic deep brain stimulation reduces premotor-motor facilitation in Parkinson's disease.

INTRODUCTION: Deep brain stimulation improves motor symptoms in Parkinson's disease and changes primary motor cortex excitability, but how subthalamic nucleus stimulation affects premotor-motor cortical connectivity remains unclear. METHODS: We investigated 10 Parkinson patients in whom single subthalamic nucleus stimulation was time-locked to transcranial magnetic dual-coil, paired-pulse stimulation of the dorsal premotor and primary motor cortex. Premotor-motor interaction with deep brain stimulation switched off was compared to 10 controls. RESULTS: Parkinson patients showed abnormally facilitated premotor-motor interaction with deep brain stimulation switched off compared to controls. This abnormal premotor-motor facilitation was abolished during subthalamic nucleus stimulation at 3 Hz. CONCLUSIONS: In Parkinson's disease, aberrant signals from the basal ganglia leading to a loss of physiological premotor-motor inhibition can be normalized by subthalamic deep brain stimulation. This effect is likely mediated by activation of subthalamic-pallidal-thalamic projection to the premotor cortex.

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.

Subclinical recurrent neck pain and its treatment impacts motor training-induced plasticity of the cerebellum and motor cortex.

The cerebellum processes pain inputs and is important for motor learning. Yet, how the cerebellum interacts with the motor cortex in individuals with recurrent pain is not clear. Functional connectivity between the cerebellum and motor cortex can be measured by a twin coil transcranial magnetic stimulation technique in which stimulation is applied to the cerebellum prior to stimulation over the motor cortex, which inhibits motor evoked potentials (MEPs) produced by motor cortex stimulation alone, called cerebellar inhibition (CBI). Healthy individuals without pain have been shown to demonstrate reduced CBI following motor acquisition. We hypothesized that CBI would not reduce to the same extent in those with mild-recurrent neck pain following the same motor acquisition task. We further hypothesized that a common treatment for neck pain (spinal manipulation) would restore reduced CBI following motor acquisition. Motor acquisition involved typing an eight-letter sequence of the letters Z,P,D,F with the right index finger. Twenty-seven neck pain participants received spinal manipulation (14 participants, 18-27 years) or sham control (13 participants, 19-24 years). Twelve healthy controls (20-27 years) also participated. Participants had CBI measured; they completed manipulation or sham control followed by motor acquisition; and then had CBI re-measured. Following motor acquisition, neck pain sham controls remained inhibited (58 ± 33% of test MEP) vs. healthy controls who disinhibited (98 ± 49% of test MEP, P<0.001), while the spinal manipulation group facilitated (146 ± 95% of test MEP, P<0.001). Greater inhibition in neck pain sham vs. healthy control groups suggests that neck pain may change cerebellar-motor cortex interaction. The change to facilitation suggests that spinal manipulation may reverse inhibitory effects of neck pain.

Influence of inter-train interval on the plastic effects of rTMS.

BACKGROUND: High frequency repetitive transcranial magnetic stimulation (rTMS) elicits plastic effects in excitatory and inhibitory circuits. Inter-train intervals (ITI) were initially incorporated into rTMS paradigms to avoid overheating and for safety considerations. Recent studies have shown that inclusion of ITI, as opposed to continuous stimulation, is essential for eliciting excitatory effects, but the optimal ITI remains unknown. Moreover, if ITI duration has no effect, it may be possible to substantially reduce treatment time for rTMS. HYPOTHESIS: ITI duration modulates the excitatory and disinhibitory effects of rTMS. METHODS: rTMS (20 Hz, 2 s trains, 1200 pulses, 100% RMT) was applied in 14 healthy individuals with ITI of 4s (duration: ∼3 min), 8s (∼5 min), 16s (∼9 min) or 32s (16.5 min) in sessions separated by ≥5 days. Effects on cortical excitability and GABAA receptor mediated short interval intracortical inhibition (SICI) were measured for 75 min following rTMS. RESULTS: The time-course of increased cortical excitability following rTMS was independent of ITI duration. There was a striking influence of ITI on SICI, whereby disinhibition increased with shorter ITI duration. Changes in cortical excitability and SICI were independent of each other. CONCLUSION: These findings provide the first evidence to suggest that ITI may be substantially shortened without loss of rTMS effects, and warrant further investigation where rTMS is applied therapeutically. Furthermore, shorter ITIs result in greater disinhibitory effects which may be desirable in some clinical disorders and accelerated treatment paradigms. The tuning of the plasticity of cortical excitatory and inhibitory circuits to rTMS parameters in human cortex are independent.

The effects of upper limb posture and a sub-maximal gripping task on corticospinal excitability to muscles of the forearm.

Variations in handgrip force influences shoulder muscle activity, and this effect is dependent upon upper limb position. Previous work suggests that neural coupling between proximal and distal muscles with changes in joint position is a possible mechanism but these studies tend to use artificially constrained postures that do not reflect activities of daily living. The purpose of this study was to examine the effects of upper limb posture on corticospinal excitability to the forearm muscles during workplace relevant arm positions. Motor evoked potentials (MEPs) were elicited in four forearm muscles via transcranial magnetic stimulation at six arm positions (45°, 90° and 120° of humeral elevation in both the flexion and abduction planes). MEPs were delivered as stimulus-response curves (SRCs) at rest and at constant intensity during two gripping tasks. Boltzmann plateau levels were smaller for the flexor carpi radialis in flexion at 45° versus 90° (p=0.0008). Extensor carpi radialis had a greater plateau during flexion than abduction (p=0.0042). Corticospinal excitability to the forearm muscles were influenced by upper limb posture during both the resting and gripping conditions. This provides further evidence that upper limb movements are controlled as a whole rather than segmentally and is relevant for workplace design considerations.

Influence of Subclinical Neck Pain on the Ability to Perform a Mental Rotation Task: A 4-Week Longitudinal Study With a Healthy Control Group Comparison.

OBJECTIVE: Mental rotation of objects and the frame of reference of those objects are critical for executing correct and skillful movements and are important for object recognition, spatial navigation, and movement planning. The purpose of this longitudinal study was to compare the mental rotation ability of those with subclinical neck pain (SCNP) to healthy controls at baseline and after 4 weeks. METHODS: Twenty-six volunteers (13 SCNP and 12 healthy controls) were recruited from a university student population. Subclinical neck pain participants had scores of mild to moderate on the Chronic Pain Grade Scale, and controls had minimal or no pain. For the mental rotation task, participants were presented with an object (letter "R") on a computer screen presented randomly in either normal or backwards parity at various orientations (0°, 45°, 90°, 135°, 180°, 225°, 270°, and 315°). Participants indicated the object's parity by pressing "N" for normal or "B" for backwards. Each orientation for normal and backward parities was presented 5 times, and the average response time for all letter presentations was calculated for each participant, at baseline and 4 weeks later. RESULTS: Both groups had overall improved response times from baseline to 4 weeks. Healthy participants had significantly improved response times compared to SCNP, both at baseline (P < .05) and 4 weeks (P < .05). CONCLUSIONS: Healthy participants performed better than the SCNP group at both time points. Subclinical neck pain may impair the ability to perform a complex mental rotation task involving cerebellar connections, possibly due to altered body schema.

A novel protocol to investigate motor training-induced plasticity and sensorimotor integration in the cerebellum and motor cortex.

Our group set out to develop a sensitive technique, capable of detecting output changes from the posterior fossa following a motor acquisition task. Transcranial magnetic stimulation (TMS) was applied over the right cerebellar cortex 5 ms in advance of test stimuli over the left cerebral motor cortex (M1), suppressing test motor-evoked potentials (MEPs) recorded in a distal hand muscle. Ten participants typed the letters Z, D, F, and P in randomized 8-letter sequences for ∼15 min, and 10 participants took part in the control condition. Cerebellar-M1 recruitment curves were established before and after the motor acquisition task. Cerebellar inhibition at 50% (CBI50) was defined as the intensity of cerebellar-M1 stimulations that produced MEPs that were 50% of the initial test MEP. Collection also occurred at stimulator intensities 5 and 10% above CBI50. A significant interaction effect of group (experimental and control) vs. time (pre- and postintervention) was observed [F(1,18) = 4.617, P = 0.046]. Post hoc tests showed a significant effect for the learning task in the experimental group [F(1,9) = 10.28, P = 0.01]. Further analysis showed specific disinhibition at CBI50 (P = 0.04), CBI50+5% (P = 0.008), and CBI50+10% (P = 0.01) for the experimental group only. Reaction time (P < 0.001) and accuracy (P = 0.006) improved significantly following practice, implying that disinhibition coincides with motor learning. No changes, however, were seen in the control condition. We conclude that this protocol is a sensitive technique that may be used to study cerebellar disinhibition with motor acquisition in vivo.

Alterations in cortical and cerebellar motor processing in subclinical neck pain patients following spinal manipulation.

OBJECTIVE: The purpose of this study was investigate whether there are alterations in cerebellar output in a subclinical neck pain (SCNP) group and whether spinal manipulation before motor sequence learning might restore the baseline functional relationship between the cerebellum and motor cortex. METHODS: Ten volunteers were tested with SCNP using transcranial magnetic stimulation before and after a combined intervention of spinal manipulation and motor sequence learning. In a separate experiment, we tested 10 healthy controls using the same measures before and after motor sequence learning. Our transcranial magnetic stimulation measurements included short-interval intracortical inhibition, long-interval intracortical inhibition, and cerebellar inhibition (CBI). RESULTS: The SCNP group showed a significant improvement in task performance as indicated by a 19% decrease in mean reaction time (P < .0001), which occurred concurrently with a decrease in CBI following the combined spinal manipulation and motor sequence learning intervention (F1,6 = 7.92, P < .05). The control group also showed an improvement in task performance as indicated by a 25% increase in reaction time (P < .001) with no changes to CBI. CONCLUSIONS: Subclinical neck pain patients have altered CBI when compared with healthy controls, and spinal manipulation before a motor sequence learning task changes the CBI pattern to one similar to healthy controls.