Effect of subthalamic nucleus deep brain stimulation on axial motor control and protective arm responses in Parkinson's disease.

Stereotactic surgical interventions for Parkinson's disease (PD) can considerably improve appendicular motor signs, but their effect on axial motor signs--especially balance control under optimal drug therapy--remains unclear. Here, we investigated the effect of bilateral subthalamic nucleus (STN) stimulation on levodopa-resistant axial and appendicular postural impairment in PD. Fourteen patients (11 with young-onset PD) and 18 age-matched controls were included. Patients were tested after intake of a suprathreshold levodopa dose, ensuring optimal response to drug therapy, and with stimulators both turned on and off. Balance control was assessed using multidirectional dynamic posturography. Outcome measures included full body kinematics and surface electromyography of paraspinal and deltoid muscles. Patients with stimulators turned off showed early decreased trunk roll with a loss of directional dependency, followed by increased and abnormally directed--i.e. destabilizing--trunk roll. Pelvis pitch motion showed decreased directional dependency in these patients. The abnormal trunk motion was not corrected by STN stimulation, but directional dependency of both trunk and pelvis motion partially improved, along with a general decrease in muscle activity. Even with stimulators off, protective arm movements were similar in the optimally treated patients and controls, indicating that these appendicular signs respond better to dopaminergic treatment than axial motor control. Our findings indicate that instability in PD results from a reduced flexibility of the trunk and pelvis that is largely resistant to STN stimulation combined with optimal drug treatment. These postural abnormalities are therefore likely associated with non-dopaminergic pathology. In contrast, protective arm movements did appear to be levodopa-responsive. Future studies should focus on identifying subgroups of optimal responders, particularly patients with levodopa-induced dyskinesias.

Variability of the subthalamic nucleus: the case for direct MRI guided targeting.

Because of concerns about direct visualization of the subthalamic nucleus (STN) on magnetic resonance imaging (MRI), many functional neurosurgeons continue to rely on atlas-based coordinates to reach this target. T2-weighted MRI does allow direct visualisation of the STN. In order to compare the coordinates of the target point within the visualised STN with those obtained from standard brain atlases, the preoperative stereotactic T2-weighted MRI used to implant 55 deep brain stimulation electrodes in the visualised STN of 29 consecutive patients with Parkinson's disease treated in two European centres were studied. The coordinates of the directly visualised STN were significantly different from those of the atlas target. Variability of the position of the STN may render direct visualisation a more accurate means of targeting this nucleus.

Activation of the subthalamic region during emotional processing in Parkinson disease.

OBJECTIVE: To elucidate the involvement of the human subthalamic nucleus (STN) region in the processing or transmission of emotional information. METHODS: Local field potentials (LFPs) were recorded from this region in 10 patients with Parkinson disease (PD) undergoing bilateral implantation of the STN for high-frequency stimulation. LFP recordings were made while patients viewed pleasant and unpleasant emotionally arousing and neutral pictures. RESULTS: A significant decrease (event-related desynchronization [ERD]) in the local alpha power (8 to 12 Hz) was found for all stimulus categories starting at about 0.5 seconds after stimulus presentation. However, 1 to 2 seconds poststimulus, the ERD was larger in trials of pleasant (mean ERD: 21.6 +/- 2.8%; p < 0.009) and unpleasant (mean ERD: 15.0 +/- 4.2%; p = 0.018) stimuli compared with neutral stimuli (mean ERD: 4.4 +/- 4.2%). CONCLUSION: The delayed modulation of alpha activity recorded from the area of the subthalamic nucleus in PD may reflect the processing or transmission of information related to emotional stimuli. "Limbic" activation in the region of the subthalamic nucleus may explain why high-frequency stimulation of the subthalamic nucleus alters affect in some patients with PD.

PET and SPECT functional imaging studies in Parkinsonian syndromes: from the lesion to its consequences.

Functional imaging techniques provide major insights into understanding the pathophysiology, progression, complications, and differential diagnosis of Parkinson's disease (PD). The dopaminergic system has been particularly studied allowing now early, presymptomatic diagnoses, which is of interest for future neuroprotective strategies. The existence of a compensatory hyperactivity of dopa-decarboxylase at disease onset has been recently demonstrated in the nigrostriatal and also extrastriatal dopaminergic pathways. Modification of dopamine receptors expression is observed during PD, but the respective contribution of dopaminergic drugs and the disease process towards these changes is still debated. Abnormalities of cerebral activation are seen and are clearly task-dependent, but the coexistence of hypoactivation in some areas and hyperactivation in others is also now well established. Such hyperactivation may be compensatory but could also reflect an inability to select appropriate motor circuits and inhibit inappropriate ones by PD patients. Interestingly, dopaminergic medications or surgical therapy reverse such abnormalities of brain activation.

Striatal contribution to cognition: working memory and executive function in Parkinson's disease before and after unilateral posteroventral pallidotomy.

The basal ganglia are intimately connected to the frontal cortex via five fronto-striatal circuits. While the role of the frontal cortex in cognition has been extensively studied, the contribution of the basal ganglia to cognition has remained less clear. In Parkinson's disease, posteroventral pallidotomy (PVP) involves surgical lesioning of the internal section of the globus pallidus (GPi, the final output pathway from the basal ganglia) to relieve the motor symptoms of the disorder. PVP in Parkinson's disease provides a unique opportunity to investigate the impact of disruption of striatal outflow to the frontal cortex on cognition. We assessed executive function and working memory after withdrawal of medication in 13 patients with Parkinson's disease before and 3 months after unilateral PVP compared to 12 age- and IQ-matched normals assessed twice with an interval of 3 months. The tests used were: Wisconsin Card Sorting (WCST), Self-Ordered Random Number Sequences, Missing Digit Test, Paced Visual Serial Addition Test (PVSAT), and Visual Conditional Associative Learning Test (VCALT). After PVP, the patients performed significantly better on the Self-Ordered Random Number Sequences and the WCST, an improvement that was also observed in the normals across the two assessment and is therefore likely to reflect practice effects. Relative to the normals, the patients showed significant differential change following PVP on the Missing Digit Test and PVSAT, on which they performed worse after compared to before surgery, while the controls performed better on the second assessment. For the patients, performance on the VCALT also indicated deterioration after PVP, but the changes approached significance. The side of PVP had no effect on the results. The pattern of change observed 3 months after PVP was maintained at 15-month follow-up. The results suggest that striatal outflow to the frontal cortex may be essential for those aspects of executive function that showed deterioration after PVP.

Intermuscular coherence in Parkinson's disease: relationship to bradykinesia.

We hypothesised that bradykinesia may be partly due to the failure of the corticomuscular system to engage in high frequency oscillatory activity in Parkinson's disease (PD). In healthy subjects such oscillations are evident in coherence between active muscles at 15--30 Hz. We therefore investigated the effects of therapeutic stimulation of the basal ganglia on this coherence and related it to changes in bradykinesia in the contralateral arm. Increases in coherence at 15--30 Hz and improvements in bradykinesia upon stimulation were correlated (r = 0.564, p < 0.001). This suggests that the basal ganglia modulate oscillatory activity in the corticomuscular system and that impairment of the motor system's ability to engage in synchronised oscillations at high frequency may contribute to bradykinesia in PD.

Intermuscular coherence in Parkinson's disease: effects of subthalamic nucleus stimulation.

It remains unclear how high frequency stimulation of the subthalamic nucleus (STN) improves parkinsonism. We hypothesized that stimulation may affect the organization of the cortical drive to voluntarily activated muscle. Normally this is characterized by oscillations at 15-30 Hz, manifest in coherence between muscles in the same frequency band. We therefore investigated the effects of STN stimulation on electromyographic (EMG) activity in co-contracting distal arm muscles in nine subjects with Parkinson's disease off drugs. Without stimulation, coherence between EMG signals was diminished at 15-30 Hz compared with nine controls. STN stimulation increased coherence in the 15-30 Hz band, so that it approached that in healthy subjects. The results suggest that STN stimulation facilitates the normal cortical drive to muscles.

Subthalamic nucleus, sensorimotor cortex and muscle interrelationships in Parkinson's disease.

Ten patients with Parkinson's disease were seen following bilateral or unilateral implantation of macroelectrodes into the subthalamic nucleus. Local field potentials (LFPs) were recorded from adjacent subthalamic nucleus macroelectrode (STNME) contacts simultaneously with EEG activity over the supplementary motor (Cz-FCz) and sensorimotor (C3/4-FC3/4) areas and EMG activity from the contralateral wrist extensors during isometric and phasic wrist movements. Significant coherence was seen between STNME LFPs and Cz-FCz, STNME LFPs and C3/4-FC3/4, and STNME LFPs and EMG over the range 7-45 Hz. EEG phase-led STNME LFPs by 24.4 ms (95% confidence interval 19.8 to 29.0 ms). EMG also led STNME LFPs, but time differences tended to cluster around one of two values: 6.3 ms (-0.7 to 13.3 ms) and 46.5 ms (26.2 to 66.8 ms). Recordings from the STNME contact that demonstrated the most consistent coherence with Cz-FCz in the 15-30 Hz band coincided with the contact which, when electrically stimulated at high frequencies, produced the most effective clinical response in eight out of nine (89%) subjects (P < 0.01). Oscillatory activity at 15-30 Hz may therefore prove of use in localizing the subthalamic nucleus target that provides the best clinical effect on stimulation. These results extend the hypothesis that coherent activity may be useful in binding together related activities in simultaneously active motor centres. The presence of coherence between EEG and STNME LFPs in both the beta and the gamma band (as opposed to only the beta band between EEG and cerebellar thalamus) suggests that there may be some relative frequency selectivity in the communication between different motor structures.

Coherence between cerebellar thalamus, cortex and muscle in man: cerebellar thalamus interactions.

Local field potentials (LFPs) were recorded in seven unanaesthetized patients between the four adjacent contacts of a macroelectrode stereotactically implanted for the treatment of tremor. The LFPs were presumed to arise predominantly from the nucleus ventralis intermedius (Vim) of the thalamus, the implantation target. They were recorded simultaneously with the ipsilateral EEG and contralateral EMG during an isometric contraction or at rest. The patients had a history of either isolated tremor (essential tremor, n = 2; benign tremulous Parkinson's disease, n = 1) or tremor with signs of a cerebellar syndrome (multiple sclerosis, n = 3; essential tremor and ataxia, n = 1), although clinical tremor was absent at the time of recording because of a temporary microthalamotomy effect in four patients. In patients with isolated tremor, oscillatory activity picked up by contacts in Vim (cerebellar thalamus) was invariably coherent with that in the sensorimotor cortex or contracting muscle in the 8-27 Hz range. Such coherence was absent in two of the four subjects with tremor associated with a cerebellar syndrome. Coherence between LFPs recorded from more caudally placed contacts and the sensorimotor cortex or contracting muscle was negligible in all patients. These caudally placed contacts demonstrated the highest sensory evoked potential in response to median nerve stimulation. Oscillatory activity in the cerebellar thalamus (Vim) lagged behind that in both cortex and muscle. Coherent activity between the cerebellar thalamus (Vim) and the cortex persisted at rest. It is suggested that rhythmicities in the 8-27 Hz range could provide the basis for a temporal framework that is widely distributed within the motor system.

The impact of deep brain stimulation on executive function in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) improves Parkinson's disease and increases frontal blood flow. We assessed the effects of bilateral DBS on executive function in Parkinson's disease patients, seven with electrodes implanted in the STN and six in the GPi. Patients were assessed off medication with stimulators off, on and off again. The groups showed differential change with stimulation on the Reitan Trail-Making test (TMT B) (STN more improved) and on some measures of random number generation and Wisconsin Card Sorting (STN improved, GPi worse with stimulation). Across the groups, stimulation speeded up responding (Stroop control trial, TMT A) and improved performance on paced serial addition and missing digit tests. Conversely, conditional associative learning became more errorful with stimulation across the two groups. In general, change in performance with stimulation was significant for the STN but not the GPi group. These results support two opposite predictions. In support of current models of Parkinson's disease, 'releasing the brake' on frontal function with DBS improved aspects of executive function. Conversely, disruption of basal ganglia outflow during DBS impaired performance on tests requiring changing behaviour in novel contexts as predicted by Marsden and Obeso in 1994.

Thalamic, subthalamic nucleus and internal pallidum stimulation in Parkinson's disease.

The limits of drug therapy in severe forms of Parkinson's disease have lead to a renewal of functional neurosurgery of the basal ganglia and the thalamus. Deep brain stimulation (DBS) of these structures was developed with the aims of reducing the morbidity of surgery and of offering an adaptative treatment. DBS was first applied to the thalamus in patients with severe tremor. Tremor of the hemibody is greatly reduced by stimulation of the contralateral electrode in 85% of the cases. There is little change in other symptoms. However, motor fluctuations and dyskinesias are a more frequent problem than severe tremor; in attempt to treat these symptoms, DBS has recently been applied to the subthalamic nucleus (STN) and the internal pallidum (GPi). STN stimulation greatly decreases off motor symptoms and motor fluctuations, which allows a reduction of drug dosage and consequently of dyskinesias. GPi stimulation decreases dyskinesias in most patients, but the effect on off motor symptoms is more variable from one series to another, from very good to nil. The severe morbidity of DBS applied to these 3 targets is low. Comparative studies of the cost and the efficacy of DBS and lesions applied to these different targets are now required.