Localization of beta and high-frequency oscillations within the subthalamic nucleus region.

Parkinsonian bradykinesia and rigidity are typically associated with excessive beta band oscillations in the subthalamic nucleus. Recently another spectral peak has been identified that might be implicated in the pathophysiology of the disease: high-frequency oscillations (HFO) within the 150-400 Hz range. Beta-HFO phase-amplitude coupling (PAC) has been found to correlate with severity of motor impairment. However, the neuronal origin of HFO and its usefulness as a potential target for deep brain stimulation remain to be established. For example, it is unclear whether HFO arise from the same neural populations as beta oscillations. We intraoperatively recorded local field potentials from the subthalamic nucleus while advancing DBS electrodes in 2 mm steps from 4 mm above the surgical target point until 2 mm below, resulting in 4 recording sites. Data from 26 nuclei from 14 patients were analysed. For each trajectory, we identified the recording site with the largest spectral peak in the beta range (13-30 Hz), and the largest peak in the HFO range separately. In addition, we identified the recording site with the largest beta-HFO PAC. Recording sites with largest beta power and largest HFO power coincided in 50% of cases. In the other 50%, HFO was more likely to be detected at a more superior recording site in the target area. PAC followed more closely the site with largest HFO (45%) than beta power (27%). HFO are likely to arise from spatially close, but slightly more superior neural populations than beta oscillations. Further work is necessary to determine whether the different activities can help fine-tune deep brain stimulation targeting.

High resolution MR anatomy of the subthalamic nucleus: imaging at 9.4 T with histological validation.

Using conventional MRI the subthalamic nucleus (STN) is not clearly defined. Our objective was to define the anatomy of the STN using 9.4 T MRI of post mortem tissue with histological validation. Spin-echo (SE) and 3D gradient-echo (GE) images were obtained at 9.4 T in 8 post mortem tissue blocks and compared directly with corresponding histological slides prepared with Luxol Fast Blue/Cresyl Violet (LFB/CV) in 4 cases and Perl stain in 3. The variability of the STN anatomy was studied using internal reference points. The anatomy of the STN and surrounding structures was demonstrated in all three anatomical planes using 9.4 T MR images in concordance with LFB/CV stained histological sections. Signal hypointensity was seen in 6/8 cases in the anterior and medial STN that corresponded with regions of more intense Perl staining. There was significant variability in the volume, shape and location of the borders of the STN. Using 9.4 T MRI, the internal signal characteristics and borders of the STN are clearly defined and significant anatomical variability is apparent. Direct visualisation of the STN is possible using high field MRI and this is particularly relevant, given its anatomical variability, for planning deep brain stimulation.

Deep brain stimulation in the treatment of depression.

OBJECTIVE: To present the technique of deep brain stimulation (DBS) and to evaluate the studies conducted on DBS in the treatment of therapy-refractory major depressive disorder (MDD). METHOD: A review of the literature on DBS in the treatment of MDD was conducted. RESULTS: The results of DBS in MDD have been presented in 2 case reports and 3 studies of 47 patients operated upon in 5 different target areas. Positive effects have been presented in all studies and side effects have been minor. DBS in the nucleus accumbens resulted in a mean reduction of Hamilton depression rating scale (HDRS) of 36% after 1 year and 30% of the 10 patients achieved remission. DBS in the internal capsule/ventral striatum resulted in a reduction of 44% after 1 year, and at the last evaluation after in mean 2 years, 40% of the 15 patients were in remission. The 20 patients with subcallosal cingulated gyrus DBS had a reduction of HDRS of 52% after 1 year, and 35% were within 1 point from remission or in remission. CONCLUSION: DBS is a promising treatment for therapy-refractory MDD. The published experience is, however, limited, and the method is at present an experimental therapy.

Effects of subthalamic stimulation on speech of consecutive patients with Parkinson disease.

OBJECTIVE: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson disease (PD). Following STN-DBS, speech intelligibility can deteriorate, limiting its beneficial effect. Here we prospectively examined the short- and long-term speech response to STN-DBS in a consecutive series of patients to identify clinical and surgical factors associated with speech change. METHODS: Thirty-two consecutive patients were assessed before surgery, then 1 month, 6 months, and 1 year after STN-DBS in 4 conditions on- and off-medication with on- and off-stimulation using established and validated speech and movement scales. Fifteen of these patients were followed up for 3 years. A control group of 12 patients with PD were followed up for 1 year. RESULTS: Within the surgical group, speech intelligibility significantly deteriorated by an average of 14.2%±20.15% off-medication and 16.9%±21.8% on-medication 1 year after STN-DBS. The medical group deteriorated by 3.6%±5.5% and 4.5%±8.8%, respectively. Seven patients showed speech amelioration after surgery. Loudness increased significantly in all tasks with stimulation. A less severe preoperative on-medication motor score was associated with a more favorable speech response to STN-DBS after 1 year. Medially located electrodes on the left STN were associated with a significantly higher risk of speech deterioration than electrodes within the nucleus. There was a strong relationship between high voltage in the left electrode and poor speech outcome at 1 year. CONCLUSION: The effect of STN-DBS on speech is variable and multifactorial, with most patients exhibiting decline of speech intelligibility. Both medical and surgical issues contribute to deterioration of speech in STN-DBS patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that STN-DBS for PD results in deterioration in speech intelligibility in all combinations of medication and stimulation states at 1 month, 6 months, and 1 year compared to baseline and to control subjects treated with best medical therapy.

Parkinsonian impairment correlates with spatially extensive subthalamic oscillatory synchronization.

The local strength of pathological synchronization in the region of the subthalamic nucleus (STN) is emerging as a possible factor in the motor impairment of Parkinson's Disease (PD). In particular, correlations have been repeatedly demonstrated between treatment-induced suppressions of local oscillatory activity in the beta frequency band and improvements in motor performance. However, a mechanistic role for beta activity is brought into question by the difficulty in showing a correlation between such activity at rest and the motor deficit in patients withdrawn from medication. Here we recorded local field potential (LFP) activity from 36 subthalamic regions in 18 patients undergoing functional neurosurgery for the treatment of PD. We recorded directly from the contacts of the deep brain stimulation (DBS) electrodes as they were introduced in successive 2 mm steps, and assessed phase coherence as a measure of spatially extended, rather than local, oscillatory synchronization. We found that phase coherence in the beta frequency band correlated with the severity of Parkinsonian bradykinesia and rigidity, both in the limbs and axial body. Such correlations were frequency and site specific in so far as they were reduced when the lowermost contact of the DBS electrode was above the dorsal STN. Correlations with limb tremor occurred at sub-beta band frequencies and were more lateralized than those between beta activity and limb bradykinesia and rigidity. Phase coherence could account for up to ∼25% of the variance in motor scores between sides and patients. These new data suggest that the strength of spatially extended oscillatory synchronization, as well as the strength of local synchronization, may be worthwhile incorporating into modelling studies designed to inform surgical targeting, post-operative stimulation parameter selection and closed-loop stimulation regimes in PD. In addition, they strengthen the link between pathological synchronization and the different motor features of Parkinsonism.

Pallidal deep brain stimulation in the treatment of Meige syndrome.

BACKGROUND: Pallidal deep brain stimulation (DBS) of globus pallidus internus (Gpi) has emerged as an effective treatment for dystonia. The experience is however limited concerning focal dystonias and to date only a few cases of pallidal DBS in the treatment of Meige syndrome have been published. METHODS/RESULTS: We here present a patient with Meige syndrome in whom unilateral pallidal DBS failed to improve the axial symptoms, but bilateral stimulation resulted in a major improvement. The Burke-Fahn-Marsden score (BFM) improved by 71.5% and the patient's blepharospasm was abolished. CONCLUSIONS: The results suggest bilateral pallidal DBS may be an effective treatment for Meige syndrome.

Multicentre European study of thalamic stimulation for parkinsonian tremor: a 6 year follow-up.

AIM: To evaluate the results of ventral intermediate (Vim) thalamic deep brain stimulation (DBS) in patients with tremor predominant Parkinson's disease (PD) at 6 years post surgery. METHODS: This was a prolonged follow-up study of 38 patients from eight centres who participated in a multicentre study, the 1 year results of which have been published previously. Total scores as well as scores for individual items of the motor part and the disability part of the Unified Parkinson's Disease Rating Scale were used for evaluation. RESULTS: Tremor was still effectively controlled by DBS and appendicular rigidity and akinesia remained stable compared with baseline. Axial scores (speech, gait and postural instability), however, worsened, and in parallel the initial improvement in activities of daily living scores at the 1 year follow-up had disappeared at 6 years, despite sustained improvement of tremor. Remarkably, neither daily doses of dopaminergic medication nor fluctuations and dyskinesias had changed at 6 years compared with baseline in this particular patient group. CONCLUSION: This study confirms that patients with tremor dominant PD who do not present with fluctuations and dyskinesias may have a relatively benign progression of the disease. Vim DBS, although having no effect on akinesia and rigidity, is a relatively lenient surgical procedure and may still have a place for long term symptomatic control of PD tremor in selected patients.

Thalamic deep brain stimulation in the treatment of essential tremor: a long-term follow-up.

Deep brain stimulation (DBS) of the nucleus ventralis intermedius thalami (Vim) in the treatment of essential tremor (ET) is well documented concerning the acute effects. Reports of the long-term effects are, however, few and the aim of the present study was to analyse the long-term efficacy of this treatment. Nineteen patients operated with unilateral Vim-DBS were evaluated with the Essential Tremor Rating Scale (ETRS) before surgery, and after a mean time of 1 and 7 years after surgery. The ETRS score for tremor of the contralateral hand was reduced from 6.8 at baseline to 1.2 and 2.7, respectively, on stimulation at follow-up. For hand function (item 11 - 14) the score was reduced from 12.7 to 4.1 and 8.2, respectively. Vim-DBS is an efficient treatment for ET, also after many years of treatment. There is, however, a decreasing effect over time, most noticeable concerning tremor of action.

The subthalamic region is activated during valence-related emotional processing in patients with Parkinson's disease.

Visual stimuli are judged for their emotional significance based on two fundamental dimensions, valence and arousal, and may lead to changes in neural and body functions like attention, affect, memory and heart rate. Alterations in behaviour and mood have been encountered in patients with Parkinson's disease (PD) undergoing functional neurosurgery, suggesting that electrical high-frequency stimulation of the subthalamic nucleus (STN) may interfere with emotional information processing. Here, we use the opportunity to directly record neuronal activity from the STN macroelectrodes in patients with PD during presentation of emotionally laden and neutral pictures taken from the International Affective Picture System (IAPS) to further elucidate the role of the STN in emotional processing. We found a significant event-related desynchronization of STN alpha activity with pleasant stimuli that correlated with the individual valence rating of the pictures. Our findings suggest involvement of the human STN in valence-related emotional information processing that can potentially be altered during high-frequency stimulation of the STN in PD leading to behavioural complications.

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.

Changes in forearm reciprocal inhibition following pallidal stimulation for dystonia.

The authors recorded forearm H reflex reciprocal inhibition and clinical outcome in eight patients with primary torsion dystonia before and 1, 3, and 6 months after pallidal deep brain stimulation (DBS). There was progressive increase in reciprocal inhibition after surgery, which correlated with clinical improvement. The authors conclude that pallidal DBS for dystonia results in functional reorganization of the nervous system, which includes a long-term increase in spinal inhibition.

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.

Hardware-related complications of deep brain stimulation: a ten year experience.

OBJECTIVE: To analyse the occurrence of hardware-related complications in patients with deep brain stimulation (DBS), over a long period of time. METHOD: All patients operated on with DBS at our institution between 1993 and 2002 were followed with respect to adverse events related to the implanted hardware. RESULTS: One hundred and nineteen consecutive patients underwent 139 procedures with implantation of 161 electrodes. The minimum follow-up was 12 months. The follow-up time was 540 electrode-years. The rate of hardware-related complications per electrode-year was 4.3%. In total, 17 patients (15%) had 23 hardware-related complications. These included 8 electrode breakages, 4 electrode migrations, 2 stimulator migrations, 3 erosions, 2 erosions and infections, 2 infections and 2 cases of stimulator malfunction. The majority of these complications occurred during the first four years in our experience. CONCLUSIONS: DBS is a life-long therapy that requires a life-long follow-up. Increased experience and adaptation of surgical technique are the main determinants for avoidance of hardware-related complications.

Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up.

Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson's disease after some 6-12 months of treatment. Long-term results in a large number of patients have been reported only from a single study centre. We report 69 Parkinson's disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3-4 years after surgery. The primary outcome measure was the change in the 'off' medication score of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) at 3-4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the 'off' medication UPDRS-III score at 3-4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the 'on' time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3-4 years showed a significant worsening in the 'on' medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3-4 years in a large cohort of patients with severe Parkinson's disease.

A 10-year follow-up review of patients who underwent Leksell's posteroventral pallidotomy for Parkinson disease.

OBJECT: The clinical condition of patients with Parkinson disease (PD) who had undergone posteroventral pallidotomy (PVP) between 1985 and 1990 was evaluated at a mean of 10 years postsurgery. These patients were part of a larger series described in the first paper on Leksell's PVP that was published in 1992. METHODS: Thirteen consecutive patients who had undergone pallidotomy at the University Hospital of Northern Sweden were tracked. Hospital and clinic records that had been updated regularly by the patients' various neurologists, geriatricians, and other clinicians were reviewed. Emphasis was placed on assessing the evolution of PD symptoms after surgery, and changes in the general health and social condition of the patients. The mean follow-up duration was 10.5 years (range 3-13.5 years). Five patients underwent a total of seven subsequent surgeries for their PD, 4 months to 11 years after the initial pallidotomy. The mean Hoehn and Yahr stage was 3 at the first surgery and 3.7 at the last follow-up review (p < 0.005). Dosages of levodopa and dopamine agonists were increased in all patients, without recurrence or induction of dyskinesias contralateral to the pallidotomy. Contralateral tremor, if it was initially controlled by surgery, remained improved. However, most patients exhibited a gradual recurrence of akinesia and an increase in gait freezing. Cognitive decline and presentation with diseases unrelated to PD were not uncommon. CONCLUSIONS: The long-term effect of PVP on dyskinesias was not only curative but also appeared to be prophylactic. Contralateral tremor was improved in the majority of patients, although additional surgeries for PD were needed in some patients. Further progression of axial and akinetic symptoms, and an eventual decline in cognition together with other concomitant illnesses, contributed to increased disability in several patients.

Dilated perivascular spaces in the putamen and pallidum in patients with Parkinson's disease scheduled for pallidotomy: a comparison between MRI findings and clinical symptoms and signs.

Forty patients with Parkinson's disease without mental deterioration who were scheduled for ventroposterolateral (VPL) pallidotomy were randomly selected for retrospective stereotactic magnetic resonance image (MRI) analysis. The preoperative MRI study was performed on a 1.0-T MRI machine with a three-dimensional gradient-echo sequence. The MRI analysis was focused on five consecutive 2 mm thick axial slices without gap and parallel to the intercommissural line, starting from the level of the foramen of Monro and continuing in a ventral direction. Lacunar cysts of varying sizes (4-424 mm3) were seen at least in one hemisphere of all patients. The cysts had a clear dominance in posteroventral regions of the lateral-most pallidal regions (GP) and posteroventral regions of the putamen (PUT). No statistical correlation was found between the number or volume of the cysts and the sex, age, or duration of illness of the patients. Patients with predominantly left-sided clinical symptoms had a concentration of the cysts in the left GP, whereas those with predominantly right-sided symptoms had cysts significantly larger and more frequent in the right than the left GP. The cysts did not seem to affect the clinical outcome of pallidotomy. The authors think striatopallidal cysts develop from dilated perivascular spaces of the lenticulostriate vessels in the posteroventral regions of the GP and PUT. They are not pathognomonic for PD, but they may play some role in lateralization of the clinical symptoms in this classically asymmetric condition.