Reduced SMA-M1 connectivity in older than younger adults measured using dual-site TMS.

With advancing age comes a decline in voluntary movement control. Growing evidence suggests that an age-related decline in effective connectivity between the supplementary motor area and primary motor cortex (SMA-M1) might play a role in an age-related decline of bilateral motor control. Dual-site transcranial magnetic stimulation (TMS) can be used to measure SMA-M1 effective connectivity. In the current study, we aimed to (1) replicate previous dual-site TMS research showing reduced SMA-M1 connectivity in older than younger adults and (2) examine whether SMA-M1 connectivity is associated with bilateral motor control in independent samples of younger (n = 30) and older adults (n = 30). SMA-M1 connectivity was measured using dual-site TMS with interstimulus intervals of 6, 7 and 8 ms, and bilateral motor control was measured using the Purdue Pegboard, Four Square Step Test and the Timed Up and Go task. Findings from this study showed that SMA-M1 connectivity was reduced in older than in younger adults, suggesting that the direct excitatory connections between SMA and M1 had reduced efficacy in older than younger adults. Furthermore, greater SMA-M1 connectivity was associated with better bimanual motor control in older adults. Thus, SMA-M1 connectivity in older adults might underpin, in part, the age-related decline in bilateral motor control. These findings contribute to our understanding of age-related declines in motor control and provide a physiological basis for the development of interventions to improve bimanual and bilateral motor control.

Modulation of corticomotor excitability after maximal or sustainable-rate repetitive finger movement is impaired in Parkinson's disease and is reversed by levodopa.

OBJECTIVES: In healthy subjects, fatiguing exercises induce a period of post-exercise corticomotor depression (PECD) that is absent in Parkinson's disease (PD). Our objective is to determine the time-course of corticomotor excitability changes following a 10-s repetitive index finger flexion-extension task performed at maximal voluntary rate (MVR) and a slower sustainable rate (MSR) in PD patients OFF and ON levodopa. METHODS: In 11 PD patients and 10 healthy age-matched controls, motor evoked potentials (MEPs) were recorded from the extensor indicis proprius (EIP) and first dorsal interosseous (FDI) muscles of the dominant arm immediately after the two tasks and at 2-min intervals for 10 min. RESULTS: In the OFF condition the PECD was absent in the two test muscles after both the MVR and MSR tasks. In the ON condition finger movement kinematics improved and a period of PECD comparable to that in controls was present after both tasks. CONCLUSION: The absence of PECD in PD subjects off medication indicates a persisting increase in corticomotor excitability after non-fatiguing repetitive finger movement that is reversed by levodopa. SIGNIFICANCE: Dopamine depletion is associated with impaired modulation of corticomotor excitability after non-fatiguing repetitive finger movement.

Rapid slowing of maximal finger movement rate: fatigue of central motor control?

Exploring the limits of the motor system can provide insights into the mechanisms underlying performance deterioration, such as force loss during fatiguing isometric muscle contraction, which has been shown to be due to both peripheral and central factors. However, the role of central factors in performance deterioration during dynamic tasks has received little attention. We studied index finger flexion/extension movement performed at maximum voluntary rate (MVR) in ten healthy subjects, measuring movement rate and amplitude over time, and performed measures of peripheral fatigue. During 20 s finger movements at MVR, there was a decline in movement rate beginning at 7-9 s and continuing until the end of the task, reaching 73% of baseline (P < 0.001), while amplitude remained unchanged. Isometric maximum voluntary contraction force and speed of single ballistic flexion and extension finger movements remained unchanged after the task, indicating a lack of peripheral fatigue. The timing of finger flexor and extensor EMG burst activity changed during the task from an alternating flexion/extension pattern to a less effective co-contraction pattern. Overall, these findings suggest a breakdown of motor control rather than failure of muscle force generation during an MVR task, and therefore that the mechanisms underlying the early decline in movement rate are central in origin.

Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson's disease.

Data regarding the effect of deep brain stimulation (DBS) surgery on the dopamine dysregulation syndrome (DDS), impulse control disorders (ICDs) and punding in Parkinson's disease (PD) are limited. We present a case series of 21 operated PD patients who had exhibited DDS, ICDs or punding at some stage during the disease. DDS remained unimproved or worsened post-operatively in 12/17 patients with pre-operative DDS (71%) (nine bilateral subthalamic nucleus [STN], one right-sided STN, two bilateral globus pallidus internus [GPi] DBS). DDS improved or resolved after bilateral STN DBS in 5/17 patients with pre-operative DDS. DDS apparently developed for the first time after bilateral STN DBS in two patients, although only after a latency of eight years in one case. One patient without reported pre-operative DDS or ICDs developed pathological gambling post-STN DBS. One patient had pathological gambling which resolved pre-operatively, and did not recur post-DBS. Thus, DDS, ICDs and punding may persist, worsen or develop for the first time after DBS surgery, although a minority of patients improved dramatically. Predictive factors may include physician vigilance, motor outcome and patient compliance.

Spike-timing-related plasticity is preserved in Parkinson's disease and is enhanced by dopamine: evidence from transcranial magnetic stimulation.

We sought to investigate the effects of dopamine on motor cortical plasticity in Parkinson's disease (PD) using a novel interventional transcranial magnetic stimulation protocol that targets spike-timing-dependent plasticity (iTMS). Six patients (3F, mean age 62 years) with mild-moderate PD (mean disease duration 6 years, UPDRS-off 13, UPDRS-on 3, H&Y stage 2, daily levodopa dosage 450 mg) were studied off and on levodopa on separate days. Paired TMS pulses at resting motor threshold with an inter-stimulus interval of 1.5 ms were given over the hand area of the motor cortex for 20 min at 0.2 Hz. Single-pulse motor evoked potential (MEP) amplitude and visually cued simple reaction time (SRT) were measured before and after iTMS. When on levodopa, MEP amplitude increased to 278+/-36% of baseline (p<0.01), and when off levodopa to 157+/-13% of baseline (p=0.02). All patients showed a significantly greater increase in MEP amplitude when on levodopa than off levodopa (p=0.01). SRT was reduced to 95% baseline after iTMS off levodopa (p=0.02), but did not change on levodopa. These findings indicate that motor cortex plasticity to iTMS is preserved in mild-moderate PD. The effects of this spike-timing-related TMS protocol on cortical excitability were consistent and were enhanced by levodopa. The results support the important role of dopamine in regulating synaptic plasticity and justify a larger crossover study to assess the therapeutic effects of iTMS in PD.

Validation of an EMG-driven, graphically based isometric musculoskeletal model of the cervical spine.

EMG-driven musculoskeletal modeling is a method in which loading on the active and passive structures of the cervical spine may be investigated. A model of the cervical spine exists; however, it has yet to be criterion validated. Furthermore, neck muscle morphometry in this model was derived from elderly cadavers, threatening model validity. Therefore, the overall aim of this study was to modify and criterion validate this preexisting graphically based musculoskeletal model of the cervical spine. Five male subjects with no neck pain participated in this study. The study consisted of three parts. First, subject-specific neck muscle morphometry data were derived by using magnetic resonance imaging. Second, EMG drive for the model was generated from both surface (Drive 1: N=5) and surface and deep muscles (Drive 2: N=3). Finally, to criterion validate the modified model, net moments predicted by the model were compared against net moments measured by an isokinetic dynamometer in both maximal and submaximal isometric contractions with the head in the neutral posture, 20 deg of flexion, and 35 deg of extension. Neck muscle physiological cross sectional area values were greater in this study when compared to previously reported data. Predictions of neck torque by the model were better in flexion (18.2% coefficient of variation (CV)) when compared to extension (28.5% CV) and using indwelling EMG did not enhance model predictions. There were, however, large variations in predictions when all the contractions were compared. It is our belief that further work needs to be done to improve the validity of the modified EMG-driven neck model examined in this study. A number of factors could potentially improve the model with the most promising probably being optimizing various modeling parameters by using methods established by previous researchers investigating other joints of the body.

Globus pallidus stimulation improves both motor and nonmotor aspects of quality of life in advanced Parkinson's disease.

Our purpose was to measure the change in quality of life (QoL) following deep brain stimulation of the globus pallidus interna (GPi-DBS) in advanced Parkinson 's disease (PD), and identifies any associations with changes in motor features of the disease. Eleven patients (age range 54-69 years, 2 women) underwent GPi-DBS (4 unilateral, 7 bilateral). Outcome measures included assessment of PD-specific QoL (mean 8 months postsurgery) using the PDQ-39 questionnaire, and standard motor assessments. Off-period UPDRS III motor scores fell by (43 +/- 8)% (mean +/- SEM). Dyskinesia severity was reduced on the abnormal involuntary movement scale by (80 +/- 3)% and UPDRS IVa by (58 +/- 8)%. QoL as assessed by the PDQ39SI improved by (30 +/- 5)%, with significant improvements in mobility, activities of daily living, bodily discomfort, emotional wellbeing, communication, and cognitions subscales. Bilateral and unilateral groups demonstrated equivalent PDQ39SI improvement. QoL improvement was highly correlated with dyskinesia reduction but not reduction in UPDRS score or age at surgery. GPi-DBS markedly improves QoL in advanced PD. The impacts are broad and improve QoL domains not directly affected by the motor symptoms of the disease. Reduced dyskinesia plays a major role in the improvement of QoL in GPi-DBS treated patients.

Blinded placebo crossover study of gabapentin in primary orthostatic tremor.

Primary orthostatic tremor (OT) is a rare but disabling condition characterized by leg tremor and feelings of instability during stance. Previous studies have reported a reduction in OT symptoms with gabapentin treatment. In this study, we report on the benefits of gabapentin treatment in a double-blind placebo-controlled crossover study of 6 OT patients. First, the maximally effective gabapentin dosage (600-2,700 mg/day) for each patient was determined during an initial dose-titration phase. Patients were then studied 7 days after drug withdrawal and again after two 2-week periods of treatment with either gabapentin or placebo, using force platform posturography to quantify postural sway and tremor. Other medications for OT were continued unchanged. Symptomatic response was assessed by a patient-rated severity scale and quality of life (QOL) questionnaire. All patients reported an increase in symptoms during the washout phase and symptom reduction (50%-75%) during gabapentin treatment. Tremor amplitude was reduced to 79% +/- 11% and sway area to 71% +/- 11% of the placebo state. QOL improved in all patients, no adverse drug effects were noted, and symptomatic benefit was maintained at follow-up (mean = 19 months). The findings confirm that gabapentin is an effective treatment for OT, reducing both tremor and postural instability and improving quality of life, and support its use as add-on or first-line therapy for OT.

Gabapentin can improve postural stability and quality of life in primary orthostatic tremor.

Primary orthostatic tremor (OT) is characterized by leg tremor and instability on standing. High frequency (13-18 Hz) tremor bursting is present in leg muscles during stance, and posturography has shown greater than normal sway. We report on an open-label add-on study of gabapentin in 6 patients with OT. Six patients were studied with surface electromyography, force platform posturography, and a modified Parkinson's disease questionnaire (PDQ-39) quality of life (QOL) scale before and during treatment with gabapentin 300 mg t.d.s. If on other medications for OT, these were continued unchanged. Of the 6 patients, 4 reported a subjective benefit of 50 to 75% with gabapentin, 3 of whom showed reduced tremor amplitude and postural sway of up to 70%. Dynamic balance improved in all 3 patients who completed the protocol. QOL data from 5 patients showed improvement in all cases. No adverse effects were noted. Gabapentin may improve tremor, stability, and QOL in patients with OT, and symptomatic response correlated with a reduction in tremor amplitude and postural sway. The findings confirm previous reports of symptomatic benefit with gabapentin and provide justification for larger controlled clinical trials. Further work is required to establish the optimal dosage and to validate the methods used to quantify the response to treatment.