Deep brain stimulation

During the last decade deep brain stimulation (DBS) has become a routine method for the treatment of advanced Parkinsons disease (PD), leading to striking improvements in motor function and quality of life of PD patients. It is associated with minimal morbidity. The rationale of targeting specific structures within basal ganglia such as the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) is strongly supported by the current knowledge of the basal ganglia pathophysiology, which is derived from extensive experimental work and which provides the theoretical basis for surgical therapy in PD. In particular, the STN has advanced to the worldwide most used target for DBS in the treatment of PD, due to the marked improvement of all cardinal symptoms of the disease. Moreover on-period dyskinesias are reduced in parallel with a marked reduction of the equivalent daily levodopa dose following STN–DBS. The success of the therapy largely depends on the selection of the appropriate candidate patients and on the precise implantation of the stimulation electrode, which necessitates careful imaging-based pre-targeting and extensive electrophysiological exploration of the target area. Despite the clinical success of the therapy, the fundamental mechanisms of high-frequency stimulation are still not fully elucidated. There is a large amount of evidence from experimental and clinical data that stimulation frequency represents a key factor with respect to clinical effect of DBS. Interestingly, high-frequency stimulation mimics the functional effects of ablation in various brain structures. The main hypotheses for the mechanism of high-frequency stimulation are: (1) depolarization blocking of neuronal transmission through inactivation of voltage dependent ion-channels, (2) jamming of information by imposing an efferent stimulation-driven high-frequency pattern, (3) synaptic inhibition by stimulation of inhibitory afferents to the target nucleus, (4) synaptic failure by stimulation-induced neurotransmitter depletion. As the hyperactivity of the STN is considered a functional hallmark of PD and as there is experimental evidence for STN-mediated glutamatergic excitotoxicity on neurons of the substantia nigra pars compacta (SNc), STN–DBS might reduce glutamatergic drive, leading to neuroprotection. Further studies will be needed to elucidate if STN–DBS indeed provides a slow-down of disease progression.     

Deep brain stimulation for treatment-resistant depression

Treatment-resistant depression is a severely disabling disorder with no proven treatment options once multiple medications, psychotherapy, and electroconvulsive therapy have failed. Based on our preliminary observation that the subgenual cingulate region (Brodmann area 25) is metabolically overactive in treatment-resistant depression, we studied whether the application of chronic deep brain stimulation to modulate BA25 could reduce this elevated activity and produce clinical benefit in six patients with refractory depression. Chronic stimulation of white matter tracts adjacent to the subgenual cingulate gyrus was associated with a striking and sustained remission of depression in four of six patients. Antidepressant effects were associated with a marked reduction in local cerebral blood flow as well as changes in downstream limbic and cortical sites, measured using positron emission tomography. These results suggest that disrupting focal pathological activity in limbic-cortical circuits using electrical stimulation of the subgenual cingulate white matter can effectively reverse symptoms in otherwise treatment-resistant depression.     

Subthalamic nucleus deep brain stimulation impacts language in early Parkinson's disease

Although deep brain stimulation (DBS) of the basal ganglia improves motor outcomes in Parkinson's disease (PD), its effects on cognition, including language, remain unclear. This study examined the impact of subthalamic nucleus (STN) DBS on two fundamental capacities of language, grammatical and lexical functions. These functions were tested with the production of regular and irregular past-tenses, which contrast aspects of grammatical (regulars) and lexical (irregulars) processing while controlling for multiple potentially confounding factors. Aspects of the motor system were tested by contrasting the naming of manipulated (motor) and non-manipulated (non-motor) objects. Performance was compared between healthy controls and early-stage PD patients treated with either DBS/medications or medications alone. Patients were assessed on and off treatment, with controls following a parallel testing schedule. STN-DBS improved naming of manipulated (motor) but not non-manipulated (non-motor) objects, as compared to both controls and patients with just medications, who did not differ from each other across assessment sessions. In contrast, STN-DBS led to worse performance at regulars (grammar) but not irregulars (lexicon), as compared to the other two subject groups, who again did not differ. The results suggest that STN-DBS negatively impacts language in early PD, but may be specific in depressing aspects of grammatical and not lexical processing. The finding that STN-DBS affects both motor and grammar (but not lexical) functions strengthens the view that both depend on basal ganglia circuitry, although the mechanisms for its differential impact on the two (improved motor, impaired grammar) remain to be elucidated.     

Deep brain stimulation for neurologic and neuropsychiatric disorders

In the 1960s, ablative stereotactic surgery was employed for a variety of movement disorders and psychiatric conditions. Although largely abandoned in the 1970s because of highly effective drugs, such as levodopa for Parkinson's disease (PD), and a reaction against psychosurgery, the field has undergone a virtual renaissance, guided by a better understanding of brain circuitry and the circuit abnormalities underlying movement disorders such as PD and neuropsychiatric conditions, such as obsessive compulsive disorder. High-frequency electrical deep brain stimulation (DBS) of specific targets, introduced in the early 1990s for tremor, has gained widespread acceptance because of its less invasive, reversible, and adjustable features and is now utilized for an increasing number of brain disorders. This review summarizes the rationale behind DBS and the use of this technique for a variety of movement disorders and neuropsychiatric diseases.     

Aggravated stuttering following subthalamic deep brain stimulation in Parkinson's disease - two cases

Stuttering is a speech disorder with disruption of verbal fluency which is occasionally present in patients with Parkinson's disease (PD). Long-term medical management of PD is frequently complicated by fluctuating motor functions and dyskinesias. High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment of motor fluctuations and is the most common surgical procedure in PD. Here we report the re-occurrence and aggravation of stuttering following STN-DBS in two male patients treated for advanced PD. In both patients the speech fluency improved considerably when the neurostimulator was turned off, indicating that stuttering aggravation was related to neurostimulation of the STN itself, its afferent or efferent projections and/or to structures localized in the immediate proximity. This report supports previous studies demonstrating that lesions of the basal ganglia-thalamocortical motor circuit, including the STN, is involved in the development of stuttering. In advanced PD STN-DBS is generally an effective and safe treatment. However, patients with PD and stuttering should be informed about the risk of aggravated symptoms following surgical therapy.     

Deep brain stimulation for movement and other neurologic disorders

Deep brain stimulation (DBS) was introduced as a treatment for patients with parkinsonism and other movement disorders in the early 1990s. The technique rapidly became the treatment of choice for these conditions, and is now also being explored for other diseases, including Tourette syndrome, gait disorders, epilepsy, obsessive-compulsive disorder, and depression. Although the mechanism of action of DBS remains unclear, it is recognized that DBS works through focal modulation of functionally specific circuits. The fact that the same DBS parameters and targets can be used in multiple diseases suggests that DBS does not counteract the pathophysiology of any specific disorder, but acts to replace pathologic activities in disease-affected brain circuits with activity that is more easily tolerated. Despite the progress made in the use of DBS, much remains to be done to fully realize the potential of this therapy. We describe some of the most active areas of research in this field, both in terms of exploration of new targets and stimulation parameters, and in terms of new electrode or stimulator designs.     

Parkinson's disease: recent development in therapies for advanced disease with a focus on deep brain stimulation (DBS) and duodenal levodopa infusion

Effective medical treatment for Parkinson's disease has been available for almost 40 years. After several years of treatment with L-dihydroxyphenylalanine (L-dopa, levodopa), however, fluctuations often occur. The patient may then experience random variations of the motor symptoms during the day. The medication becomes increasingly complicated. New therapeutic methods, deep brain stimulation and duodenal infusion of L-dopa, have proven to be very effective in stabilizing the fluctuations. A clinical update of Parkinson's disease is presented together with a short review of these two methods.     

Subthalamic local field beta oscillations during ongoing deep brain stimulation in Parkinson's disease in hyperacute and chronic phases

In the past years, local field potential (LFP) signals recorded from the subthalamic nucleus (STN) in patients undergoing deep brain stimulation (DBS) for Parkinson's disease (PD) disclosed that DBS has a controversial effect on STN beta oscillations recorded 2-7 days after surgery for macroelectrode implantation. Nothing is known about these DBS-induced oscillatory changes 30 days after surgery. We recorded STN LFPs during ongoing DBS in 7 patients with PD, immediately (hyperacute phase) and 30 days (chronic phase) after surgery. STN LFP recordings showed stationary intranuclear STN beta LFP activity in hyperacute and chronic phases, confirming that beta peaks were also present in chronic recordings. Power spectra of nuclei with significant beta activity (54% of the sample) showed that it decreased significantly during DBS (p=0.021) under both recording conditions. The time course of beta activity showed more evident DBS-induced changes in the chronic than in the hyperacute phase (p=0.014). DBS-induced changes in STN beta LFPs in patients undergoing DBS in chronic phase provide useful information for developing a new neurosignal-controlled adaptive DBS system.     

Deep brain stimulation: eye movements reveal anomalous effects of electrode placement and stimulation

One of the major difficulties in evaluating the efficacy of deep brain stimulation (DBS), or understanding its mechanism, is the need to distinguish the effects of stimulation itself from those of the lesion inevitably created during surgery. Recent work has shown that DBS of the subthalamic nucleus in Parkinson's disease greatly reduces the time it takes the eyes to make a saccade in response to a visual stimulus. Since this saccadic latency can be rapidly and objectively measured, we used it to compare the effects of surgery and of stimulation. We used a saccadometer to measure the saccadic latencies of 9 DBS patients (1) preoperatively, (2) the day after insertion of subthalamic nucleus electrodes, (3) three weeks later, prior to turning on the stimulator, and (4) after commencement of stimulation. Patients were on their anti-Parkinsonian medication throughout the study. It revealed an entirely unexpected and puzzling finding. As in previous studies an amelioration of symptoms is seen immediately after surgery, and then a further improvement when finally the stimulator is turned on, but in the case of saccadic latency the pattern is different: surgery produces a transient increase in latency, returning to baseline within three weeks, while subsequent stimulation reduced latency. Thus the differential effects of electrode placement and stimulation are completely different for saccades and for more general motor symptoms. This important finding rules out some over-simple interpretations of the mechanism of DBS, and needs to be taken into account in future attempts at modelling the neurophysiology of DBS.     

Accounting for movement increases sensitivity in detecting brain activity in Parkinson's disease

Parkinson's disease (PD) is manifested by motor impairment, which may impede the ability to accurately perform motor tasks during functional magnetic resonance imaging (fMRI). Both temporal and amplitude deviations of movement performance affect the blood oxygenation level-dependent (BOLD) response. We present a general approach for assessing PD patients' movement control employing simultaneously recorded fMRI time series and behavioral data of the patients' kinematics using MR-compatible gloves. Twelve male patients with advanced PD were examined with fMRI at 1.5T during epoch-based visually paced finger tapping. MR-compatible gloves were utilized online to quantify motor outcome in two conditions with or without dopaminergic medication. Modeling of individual-level brain activity included (i) a predictor consisting of a condition-specific, constant-amplitude boxcar function convolved with the canonical hemodynamic response function (HRF) as commonly used in fMRI statistics (standard model), or (ii) a custom-made predictor computed from glove time series convolved with the HRF (kinematic model). Factorial statistics yielded a parametric map for each modeling technique, showing the medication effect on the group level. Patients showed bilateral response to levodopa in putamen and globus pallidus during the motor experiment. Interestingly, kinematic modeling produced significantly higher activation in terms of both the extent and amplitude of activity. Our results appear to account for movement performance in fMRI motor experiments with PD and increase sensitivity in detecting brain response to levodopa. We strongly advocate quantitatively controlling for motor performance to reach more reliable and robust analyses in fMRI with PD patients.     

Increase in body weight is a non-motor side effect of deep brain stimulation of the subthalamic nucleus in Parkinson's disease

Deep brain stimulation of the subthalamic nucleus (DBS STN) is an effective treatment method in advanced Parkinson's disease (PD) providing marked improvement of its major motor symptoms. In addition, non-motor effects have been reported including weight gain in PD patients after DBS STN. Using retrospective survey, we aimed to evaluate weight changes in our patients with advanced PD treated with DBS STN. We inquired 25 PD patients (16 men, 9 women), of mean age 55 (42-65) years, mean PD duration 15 (9-21) years, who previously received bilateral DBS STN. We obtained valid data from 23 patients. In the first survey, 1 to 45 months after DBS, weight gain was found in all patients comparing to pre-DBS period. The mean increase was 9.4 kg (from 1 to 25 kg). The patients' mean body mass index (BMI) increased from 23.7 to 27.0 kg/m2, i.e. by 3.3 kg/m2 (+2 to +6.1 kg/m2). In the repeated survey one year later, in 12 of the patients body weight moderately decreased, 3 did not change, and 6 patients further increased their weight. Possible explanations of body weight gain after DBS STN include a reduction of energy output related to elimination of dyskinesias, improved alimentation or direct influence on function of lateral hypothalamus by DBS STN.     

Deep brain stimulation of nucleus accumbens region in alcoholism affects reward processing

The influence of bilateral deep brain stimulation (DBS) of the nucleus nucleus (NAcc) on the processing of reward in a gambling paradigm was investigated using H(2)[(15)O]-PET (positron emission tomography) in a 38-year-old man treated for severe alcohol addiction. Behavioral data analysis revealed a less risky, more careful choice behavior under active DBS compared to DBS switched off. PET showed win- and loss-related activations in the paracingulate cortex, temporal poles, precuneus and hippocampus under active DBS, brain areas that have been implicated in action monitoring and behavioral control. Except for the temporal pole these activations were not seen when DBS was deactivated. These findings suggest that DBS of the NAcc may act partially by improving behavioral control.     

Deep brain stimulation: Challenges at the tissue-electrode interface and current solutions

Deep brain stimulation (DBS) is used to treat the motor symptoms of Parkinson's disease patients by stimulating the subthalamic nucleus. However, optimization of DBS is still needed since the performance of the neural electrodes is limited by the body's response to the implant. This review discusses the issues with DBS, such as placement of electrodes, foreign body response, and electrode degradation. The current solutions to these technical issues include modifications to electrode material, coatings, and geometry.