François Alesch

No tissue damage by chronic deep brain stimulation in Parkinson's disease

We report on the pathological findings in the brains of 8 Parkinsons disease patients treated with deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (6 cases) and subthalamic nucleus (2 cases). DBS was performed continuously for up to 70 months. All brains showed well‐preserved neural parenchyma and only mild gliosis around the lead track compatible with reactive changes due to surgical placement of the electrode. We conclude that chronic DBS does not cause damage to adjacent brain tissue. Ann Neurol 2000;48:372–376

Multicentre European study of thalamic stimulation in essential tremor: a six year follow up

Background: Thalamic stimulation is an efficient treatment for disabling essential tremor, as previously shown, but follow up has mostly been short term. Objectives: To see whether good results can be maintained in the longer term. Methods: 37 patients with essential tremor had implantation of a thalamic stimulator, either unilaterally or bilaterally. The results at one year have been reported earlier. After six years, 19 patients were available for follow up. The main instrument for evaluation was the essential tremor rating scale. The patients were examined with pulse generators turned on and off. Results: In the majority of patients, the very good results with stimulation seen at one year were maintained after a mean of 6.5 years. The reduction in tremor scores and improvement in activities of daily living were highly significant compared with baseline and with the stimulation turned off. There were few serious adverse events. Minor side effects related to stimulation were common. Few device related complications were observed and most could be resolved. Conclusions: Good reduction in tremor can be maintained for more than six years in the majority of these severely disabled patients. Thalamic stimulation can be recommended in essential tremor where there is insufficient response to drug treatment. Surgical procedures and follow up should be concentrated in relatively few centres, which will thereby acquire a high degree of expertise.

Treatment of severe tardive dystonia with pallidal deep brain stimulation

In five patients with medically refractory tardive dystonia, continuous bilateral high-frequency stimulation of the globus pallidus internus was associated with a rapid (within 12 to 72 hours) and substantial (mean 87%, 10.7 SD of the motor part of the Burke–Fahn–Marsden Dystonia Rating Scale) improvement of dystonia and functional disability without adverse events.

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.

Frequency-correlated decreases of motor cortex activity associated with subthalamic nucleus stimulation in Parkinson's disease

According to the classical model of basal ganglia organization, deep brain stimulation (DBS) in the subthalamic nucleus (STN) for the treatment of Parkinsons disease (PD) blocks overactive excitatory projections to inhibitory basal ganglia output structures. This would release the break on thalamofrontal neurons alleviating the poverty of movement, the hallmark of PD. Such parallels to a functional lesion certainly simplify the mechanism of STN DBS. Here, we applied parametric analyses of H2(15)O positron emission tomography (PET) scans at rest while systematically varying stimulation frequency in 6 patients with STN DBS for akinetic PD. A strong positive correlation of rCBF to increasing stimulation frequency was detected around the STN bilaterally. More importantly, we show that gradual increases in STN stimulation frequency are tightly correlated with decreases in motor cortex activity. This demonstrates an active modulation of resting activity within the subcortical stimulation target and within motor cortex by STN DBS. Rather than a possible downstream effect, we propose to consider the tight correlations between DBS frequency and motor cortex activity in the context of an upstream modulation of direct efferents to the STN from primary motor and premotor cortices.

Deep brain stimulation of the subthalamic nucleus for control of extrapyramidal features in advanced idiopathic parkinson's disease: one year follow-up.

Summary. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) with a quadripolar electrode was carried out in 9 patients with advanced idiopathic Parkinsons disease (PD) affected with severe diurnal motor fluctuations. The effect of bilateral STN stimulation was evaluated by clinical methods in all patients after 3 and 12 months.Assessment was based on the Unified Parkinsons Disease Rating Scale (UPDRS), timed motor tests, the Schwab and England Activities of Daily Living and a diary chart to document motor fluctuations. Alterations in parkinsonian signs, motor performance and functional outcome were recorded postoperatively (1) under temporary complete withdrawal of both STN stimulation and medication; (2) in the presence of STN stimulation only; and (3) in the presence of both STN stimulation and medication. The results were compared with the preoperative data assessed in defined on-phase and defined off-phase.STN stimulation on (compared to STN stimulation off) results in a significant improvement in UPDRS motor scores: after 3 months from 50.5 ± 14.3 to 27.8 ± 5.8, and after 12 months from 49.4 ± 14.1 to 27.1 ± 7.1 (p < 0.01). There was a significant decrease in the average duration of off-periods from 8.82 ± 2.47 hours to 1.00 ± 1.06 hours (p < 0.001), a marked increase in on-periods without dyskinesia from 4.62 ± 2.72 to 14.62 ± 1.51 hours (p < 0.01), and a sharp drop in on-periods with dyskinesia from 2.87 (± 4.18) to 0.25 (± 0.97) hours (p < 0.05), which remained stable up to 12 months (off-periods: 1.25 ± 1.58 hours, p < 0.001; on-periods without: 13.87 ± 1.95 hours, p < 0.001; and on-periods wth dyskinesia: 0.37 ± 1.06 hours, p < 0.05). However, our first PD patient with an implanted DBS electrode within the STN died from cardiac infarction two days after surgery. This sudden death was not linked either to surgery nor to stimulation – and happened by chance.Our findings confirm that STN stimulation is a suitable functional neurosurgical procedure for the modulation and control of PD signs associated with severe motor fluctuations, in that they demonstrate a beneficial effect which was fully sustained over a one year follow-up period.

Thalamic stimulation for essential tremor activates motor and deactivates vestibular cortex

Background: The functional effects of deep brain stimulation in the nucleus ventralis intermedius (VIM) of the thalamus on brain circuitry are not well understood. The connectivity of the VIM has so far not been studied functionally. It was hypothesized that VIM stimulation would exert an effect primarily on VIM projection areas, namely motor and parietoinsular vestibular cortex. Methods: Six patients with essential tremor who had electrodes implanted in the VIM were studied with PET. Regional cerebral blood flow was measured during three experimental conditions: with 130 Hz (effective) and 50 Hz (ineffective) stimulation, and without stimulation. Results: Effective stimulation was associated with regional cerebral blood flow increases in motor cortex ipsilateral to the side of stimulation. Right retroinsular (parietoinsular vestibular) cortex showed regional cerebral blood flow decreases with stimulation. Conclusions: Beneficial effects of VIM stimulation in essential tremor are associated with increased synaptic activity in motor cortex, possibly due to nonphysiologic activation of thalamofrontal projections or frequency-dependent neuroinhibition. Retroinsular regional cerebral blood flow decreases suggest an interaction of VIM stimulation on vestibular–thalamic–cortical projections that may explain dysequilibrium, a common and reversible stimulation-associated side effect.

Apomorphine test: a predictor for motor responsiveness to deep brain stimulation of the subthalamic nucleus.

The value of the apomorphine test as a predictor of the clinical outcome of deep brain stimulation of the subthalamic nucleus (STN) was evaluated in patients with advanced idiopathic Parkinson’s disease (IPD) or multiple system atrophy (MSA). Thirteen IPD patients with severe diurnal fluctuations and one MSA patient not responding to dopaminergic drugs were assessed with the Unified Parkinson’s Disease Rating Scale (UPDRS) and the timed finger tapping test (FTT), measured preoperatively on and off apomorphine and postoperatively on and off STN stimulation. UPDRS motor items 20–25 were assessed intraoperatively on and off STN stimulation when the clinically effective target was approached. The motor response to immediate intraoperative and long-term STN stimulation was correlated with results of the apomorphine test. The response to immediate intraoperative STN stimulation was accurately predicted by apomorphine challenge in all 13 IPD patients. Clinical outcome following long-term STN stimulation was correlated significantly with preoperative changes due to apomorphine measured with the UPDRS motor scores (r = 0.7125, P < 0.01) and FTT (r = 0.9276, P < 0.001). Moreover, comparison of long-term STN stimulation to preoperative drug treatment displayed a significant reduction in the duration of off-phases and a significant increase in the duration of on-phases. However, in the single patient with MSA no beneficial response was obtained either to apomorphine or to STN stimulation intraoperatively and during the postoperative externalized test period. Our results indicate that the apomorphine test can predict the outcome of immediate and long-term STN stimulation and may help in the selection of candidates for surgery.

Multiple-source current steering in subthalamic nucleus deep brain stimulation for Parkinson's disease (the VANTAGE study): a non-randomised, prospective, multicentre, open-label study

BACKGROUND High-frequency deep brain stimulation (DBS) with a single electrical source is effective for motor symptom relief in patients with Parkinsons disease. We postulated that a multiple-source, constant-current device that permits well defined distribution of current would lead to motor improvement in patients with Parkinsons disease. METHODS We did a prospective, multicentre, non-randomised, open-label intervention study of an implantable DBS device (the VANTAGE study) at six specialist DBS centres at universities in six European countries. Patients were judged eligible if they were aged 21-75 years, had been diagnosed with bilateral idiopathic Parkinsons disease with motor symptoms for more than 5 years, had a Hoehn and Yahr score of 2 or greater, and had a Unified Parkinsons disease rating scale part III (UPDRS III) score in the medication-off state of more than 30, which improved by 33% or more after a levodopa challenge. Participants underwent bilateral implantation in the subthalamic nucleus of a multiple-source, constant-current, eight-contact, rechargeable DBS system, and were assessed 12, 26, and 52 weeks after implantation. The primary endpoint was the mean change in UPDRS III scores (assessed by site investigators who were aware of the treatment assignment) from baseline (medication-off state) to 26 weeks after first lead implantation (stimulation-on, medication-off state). This study is registered with ClinicalTrials.gov, number NCT01221948. FINDINGS Of 53 patients enrolled in the study, 40 received a bilateral implant in the subthalamic nucleus and their data contributed to the primary endpoint analysis. Improvement was noted in the UPDRS III motor score 6 months after first lead implantation (mean 13·5 [SD 6·8], 95% CI 11·3-15·7) compared with baseline (37·4 [8·9], 34·5-40·2), with a mean difference of 23·8 (SD 10·6; 95% CI 20·3-27·3; p<0·0001). One patient died of pneumonia 24 weeks after implantation, which was judged to be unrelated to the procedure. 125 adverse events were reported, the most frequent of which were dystonia, speech disorder, and apathy. 18 serious adverse events were recorded, three of which were attributed to the device or procedure (one case each of infection, migration, and respiratory depression). All serious adverse events resolved without residual effects and stimulation remained on during the study. INTERPRETATION The multiple-source, constant-current, eight-contact DBS system suppressed motor symptoms effectively in patients with Parkinsons disease, with an acceptable safety profile. Future trials are needed to investigate systematically the potential benefits of this system on postoperative outcome and its side-effects. FUNDING Boston Scientific.

Differential modulation of subcortical target and cortex during deep brain stimulation

The combination of electrical deep brain stimulation (DBS) with functional imaging offers a unique model for tracing brain circuitry and for testing the modulatory potential of electrical stimulation on a neuronal network in vivo. We therefore applied parametric positron emission tomography (PET) analyses that allow characterization of rCBF responses as linear and nonlinear functions of the experimentally modulated stimulus (variable stimulator setting). In patients with electrodes in the thalamic ventrointermediate nucleus (VIM) for the treatment of essential tremor (ET) here we show that variations in voltage and frequency of thalamic stimulation have differential effects in a thalamo-cortical circuitry. Increasing stimulation amplitude was associated with a linear raise in rCBF at the thalamic stimulation site, but with a nonlinear rCBF response in the primary sensorimotor cortex (M1/S1). The reverse pattern in rCBF changes was observed with increasing stimulation frequency. These results indicate close connectivity between the stimulated nucleus (VIM) and primary sensorimotor cortex. Likewise, stimulation parameter-specific modulation occurs at this simple interface between an electrical and a cerebral system and suggests that the scope of DBS extends beyond an ablation-like on-off effect: DBS could rather allow a gradual tuning of activity within a neuronal circuit.