Latest view on the mechanism of action of deep brain stimulation

How does deep brain stimulation (DBS) applied at high frequency (100 Hz and above, HFS) in diverse points of cortico‐basal ganglia thalamo‐cortical loops alleviate symptoms of neurological disorders such as Parkinson's disease, dystonia, and obsessive compulsive disorders? Do the effects of HFS stem solely or even largely from local effects on the stimulated brain structure or are they also mediated by actions of HFS on distal structures? Indeed, HFS as an extracellular stimulation is expected to activate subsets of both afferent and efferent axons, leading to antidromic spikes that collide with ongoing spontaneous ones and orthodromic spikes that evoke synaptic responses in target neurons. The present review suggests that HFS interfere with spontaneous pathological patterns by introducing a regular activity in several nodal points of the network. Therefore, the best site of implantation of the HFS electrode may be in a region where the HFS‐driven activity spreads to most of the identified, dysrhythmic, neuronal populations without causing additional side effects. This should help tackling the most difficult issue namely, how does the regular HFS‐driven activity that dampens the spontaneous pathological one, restore neuronal processing along cortico‐basal ganglia‐thalamo‐cortical loops? © 2008 Movement Disorder Society     

Subthalamic deep brain stimulation for Parkinson's disease: Correlation between locations of oscillatory activity and optimal site of stimulation

Subthalamic nucleus deep brain stimulation (STN DBS) is an effective surgical treatment for Parkinson's disease (PD). Recent studies demonstrated that pathological oscillations are seen largely within the dorsolateral portion of the STN, which is the same location that predicts optimal therapeutic benefit with DBS; however, the precise nature of the relationship between these two phenomena remains unclear. The purpose of this study was to explore localization of oscillatory activity in relation to the optimal contacts of DBS which results in the best motor improvement. We studied 23 PD patients who underwent electrode implantation into the STN for motor symptoms.Microelectrode recordings were taken from the STN during surgery and neuronal activity was analyzed offline. Spectral characteristics were calculated. Clinical outcomes were evaluated pre- and post-STN DBS implantation using the Unified Parkinson's Disease Rating Scale (UPDRS III). The position of optimal electrode contacts was assessed by postoperative magnetic resonance imaging (MRI) and was compared to the location of oscillatory activity within the STN as well as its dorsal margin (where STN neuronal activity was first detected). Of the total 188 neurons obtained, 51 (27.1%) neurons showed significant oscillatory activity. Of those, 47 (92.2%) were localized in the dorsal portion of the STN. Furthermore, there was no significant difference between the averaged coordinates of the position of 40 optimal contacts and the coordinates of the dorsal margin of the STN. The data indicate that the positions of the best contacts correlate with the locations of the oscillatory neurons supporting the prediction that stimulation of the dorsolateral oscillatory region leads to an effective clinical outcome for STN DBS surgery.     

Effects of deep brain stimulation on the primary motor cortex: Insights from transcranial magnetic stimulation studies

Deep brain stimulation (DBS) implanted in different basal ganglia nuclei regulates the dysfunctional neuronal circuits and improves symptoms in movement disorders. However, the understanding of the neurophysiological mechanism of DBS is at an early stage. Transcranial magnetic stimulation (TMS) can be used safely in movement disorder patients with DBS, and can shed light on how DBS works. DBS at a therapeutic setting normalizes the abnormal motor cortical excitability measured with motor evoked potentials (MEP) produced by primary motor cortical TMS. Abnormal intracortical circuits in the motor cortex tested with paired-pulse TMS paradigm also show normalization with DBS. These changes are accompanied with improvements in symptoms after chronic DBS. Single-pulse DBS produces cortical evoked potentials recorded by electroencephalography at specific latencies and modulates motor cortical excitability at certain time intervals measured with MEP. Combination of basal ganglia DBS with motor cortical TMS at stimulus intervals consistent with the latency of cortical evoked potentials delivered in a repetitive mode produces plastic changes in the primary motor cortex. TMS can be used to examine the effects of open and closed loop DBS. Patterned DBS and TMS delivered in a repetitive mode may be developed as a new therapeutic method for movement disorder patients.     

Spatiotemporal visualization of deep brain stimulation-induced effects in the subthalamic nucleus

Deep brain stimulation (DBS) is a successful surgical therapy used to treat the disabling symptoms of movement disorders such as Parkinson's disease. It involves the chronic stimulation of disorder-specific nuclei. However, the mechanisms that lead to clinical improvements remain unclear. Consequently, this slows the optimization of present-day DBS therapy and hinders its future development and application. We used a computational model to calculate the distribution of electric potential induced by DBS and study the effect of stimulation on the spiking activity of a subthalamic nucleus (STN) projection neuron. We previously showed that such a model can reveal detailed spatial effects of stimulation in the vicinity of the electrode. However, this multi-compartmental STN neuron model can fire in either a burst or tonic mode and, in this study, we hypothesized that the firing mode of the cell will have a major impact on the DBS-induced effects. Our simulations showed that the bursting model exhibits behaviour observed in studies of high-frequency stimulation of STN neurons, such as the presence of a silent period at stimulation offset and frequency-dependent stimulation effects. We validated the model by simulating the clinical parameter settings used for a Parkinsonian patient and showed, in a patient-specific anatomical model, that the region of affected tissue is consistent with clinical observations of the optimal DBS site. Our results demonstrated a method of quantitatively assessing neuronal changes induced by DBS, to maximize therapeutic benefit and minimize unwanted side effects.     

Pallidal stimulation that improves parkinsonian motor symptoms also modulates neuronal firing patterns in primary motor cortex in the MPTP-treated monkey

Deep brain stimulation (DBS), a surgical therapy for advanced Parkinson's disease (PD), is known to change neuronal activity patterns in the pallidothalamic circuit. Whether these effects translate to the motor cortex and, if so, how they might modulate the functional responses of individual neurons in primary motor cortex remains uncertain. A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey was implanted with a DBS lead spanning internal and external segments of globus pallidus. During therapeutic stimulation (135 Hz) for rigidity and bradykinesia, neurons in primary motor cortex (M1) exhibited an inhibitory phase-locking (2–5 ms) to the stimulus, an overall decrease in mean discharge rate, and an increase in response specificity to passive limb movement. Sub-therapeutic DBS (30 Hz) still produced entrainment to the stimulation, but the mean discharge rate and specificity to movement were not changed. Lower stimulation intensities (at 135 Hz), which no longer improved motor symptoms, had little effect on M1 activity. These findings suggest that DBS improves parkinsonian motor symptoms by inducing global changes in firing pattern and rate along the pallido-thalamocortical sensorimotor circuit.     

External pallidal stimulation improves parkinsonian motor signs and modulates neuronal activity throughout the basal ganglia thalamic network

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) are effective for the treatment of advanced Parkinson's disease (PD). We have shown previously that DBS of the external segment of the globus pallidus (GPe) is associated with improvements in parkinsonian motor signs; however, the mechanism of this effect is not known. In this study, we extend our findings on the effect of STN and GPi DBS on neuronal activity in the basal ganglia thalamic network to include GPe DBS using the 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) monkey model. Stimulation parameters that improved bradykinesia were associated with changes in the pattern and mean discharge rate of neuronal activity in the GPi, STN, and the pallidal [ventralis lateralis pars oralis (VLo) and ventralis anterior (VA)] and cerebellar [ventralis lateralis posterior pars oralis (VPLo)] receiving areas of the motor thalamus. Population post-stimulation time histograms revealed a complex pattern of stimulation-related inhibition and excitation for the GPi and VA/VLo, with a more consistent pattern of inhibition in STN and excitation in VPLo. Mean discharge rate was reduced in the GPi and STN and increased in the VPLo. Effective GPe DBS also reduced bursting in the STN and GPi. These data support the hypothesis that therapeutic DBS activates output from the stimulated structure and changes the temporal pattern of neuronal activity throughout the basal ganglia thalamic network and provide further support for GPe as a potential therapeutic target for DBS in the treatment of PD.     

Pallidal burst activity during therapeutic deep brain stimulation

Theoretical and experimental analyses of deep brain stimulation (DBS) in the subthalamic nucleus (STN) show both excitatory and inhibitory effects on the neural elements surrounding the electrode. Given these observations, the mechanism underlying the therapeutic effect of STN DBS on parkinsonian motor signs remains under debate. One hypothesis suggests that abnormal levels of bursting activity in the pallidum play a key role in the development of parkinsonian motor signs and that STN DBS may exert its beneficial effect by modifying this type of activity. We quantified the changes in bursting activity of globus pallidus internus (GPi) and externus (GPe) neurons before and during ineffective (subtherapeutic) and effective (therapeutic) STN DBS in two monkeys rendered parkinsonian by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Compared to pre-stimulation control values, the population mean firing rate increased during therapeutic stimulation significantly in both GPe (from 41.7 Hz+/-2.8 to 71.4 Hz+/-7.8) and GPi (from 58.8 Hz+/-4.2 to 71.5 Hz+/-6.2). The burst rate, however, increased significantly in GPe (from 80.1 bursts/min+/-10.0 to 103.1 bursts/min+/-11.1) and decreased significantly in GPi (from 104.2 bursts/min+/-8.3 to 75.8 bursts/min+/-10.8). Although both animals showed improvement in parkinsonian motor signs, changes in rate and bursting activity in GPi were significant only in one animal. These data suggest that while changes in rate and bursting activity may contribute to the improvement in PD motor signs during STN DBS, one cannot explain the therapeutic effects of stimulation in all cases solely on changes in these parameters. Other physiological changes that contribute to its therapeutic effect must also occur.     

Hemispheric dissociation of reward processing in humans: Insights from deep brain stimulation

Rewards have various effects on human behavior and multiple representations in the human brain. Behaviorally, rewards notably enhance response vigor in incentive motivation paradigms and bias subsequent choices in instrumental learning paradigms. Neurally, rewards affect activity in different fronto-striatal regions attached to different motor effectors, for instance in left and right hemispheres for the two hands. Here we address the question of whether manipulating reward-related brain activity has local or general effects, with respect to behavioral paradigms and motor effectors. Neuronal activity was manipulated in a single hemisphere using unilateral deep brain stimulation (DBS) in patients with Parkinson's disease. Results suggest that DBS amplifies the representation of reward magnitude within the targeted hemisphere, so as to affect the behavior of the contralateral hand specifically. These unilateral DBS effects on behavior include both boosting incentive motivation and biasing instrumental choices. Furthermore, using computational modeling we show that DBS effects on incentive motivation can predict DBS effects on instrumental learning (or vice versa). Thus, we demonstrate the feasibility of causally manipulating reward-related neuronal activity in humans, in a manner that is specific to a class of motor effectors but that generalizes to different computational processes. As these findings proved independent from therapeutic effects on parkinsonian motor symptoms, they might provide insight into DBS impact on non-motor disorders, such as apathy or hypomania.     

A template subtraction method for stimulus artifact removal in high-frequency deep brain stimulation.

Deep brain stimulation (DBS) is a neurosurgical technique that has been widely applied for the treatment of tremor or motor symptoms associated with advanced Parkinson's disease. Large stimulus artifacts, however, have hampered investigations of physiological mechanisms underlying DBS effects using extracellular recording techniques. We have developed an off-line procedure for removing stimulus artifacts from recorded neuronal signals (monopolar) and applied this method of artifact subtraction to DBS studies using extracellular recording techniques in a nonhuman primate. The procedure consists of developing a template of the artifact by averaging the artifact signals triggered by its onset. The template is then subtracted from the individual triggered signals. The experimental results indicate that this method is highly effective in removing the majority of the stimulus artifact, while leaving recorded neuronal activity intact. In fact, removal of stimulation artifact using this technique has revealed a short-latency neuronal response to stimulation that was previously obscured by the stimulus artifact. Thus, this technique may not only improve the quality of electrophysiological studies employing DBS techniques, but may also help to elucidate neuronal mechanisms underlying the effect of DBS.     

Combining functional imaging with brain stimulation in Parkinson's disease

Brain stimulation techniques such as deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS) constitute promising clinical and research tools to investigate neural mechanisms underlying neurological and psychiatric diseases. They have enormous potential in modifying brain activity and subsequent function. However, it is still a matter of debate how either of these stimulation approaches operates to produce the clinical outcomes observed in patients. The combination of these techniques with functional neuroimaging is contributing significantly to disentangle the mechanisms through which brain stimulation affects neuronal activity and related networks. In the present review we outline the research done to date on the effects of DBS and TMS on motor, cognition and behaviour in Parkinson's disease (PD) with particular emphasis on neuroimaging.     

Combining functional imaging with brain stimulation in Parkinson's disease

Abstract

Brain stimulation techniques such as deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS) constitute promising clinical and research tools to investigate neural mechanisms underlying neurological and psychiatric diseases. They have enormous potential in modifying brain activity and subsequent function. However, it is still a matter of debate how either of these stimulation approaches operates to produce the clinical outcomes observed in patients. The combination of these techniques with functional neuroimaging is contributing significantly to disentangle the mechanisms through which brain stimulation affects neuronal activity and related networks. In the present review we outline the research done to date on the effects of DBS and TMS on motor, cognition and behaviour in Parkinson's disease (PD) with particular emphasis on neuroimaging.     

Closed-loop cortical neuromodulation in Parkinson’s disease: An alternative to deep brain stimulation?

Deep brain stimulation (DBS) is usually performed to treat advanced Parkinson’s disease (PD) patients with electrodes permanently implanted in basal ganglia while the stimulator delivers electrical impulses continuously and independently of any feedback (open-loop stimulation). Conversely, in closed-loop stimulation, electrical stimulation is delivered as a function of neuronal activities recorded and analyzed online. There is an emerging development of closed-loop DBS in the treatment of PD and a growing discussion about proposing cortical stimulation rather than DBS for this purpose. Why does it make sense to “close the loop” to treat parkinsonian symptoms? Could closed-loop stimulation applied to the cortex become a valuable therapeutic strategy for PD? Can mathematical modeling contribute to the development of this technique? We review the various evidences in favor of the use of closed-loop cortical stimulation for the treatment of advanced PD, as an emerging technique which might offer substantial clinical benefits for PD patients.     

Network effects of subthalamic deep brain stimulation drive a unique mixture of responses in basal ganglia output

Deep brain stimulation (DBS) is a remarkably successful treatment for the motor symptoms of Parkinson's disease. High-frequency stimulation of the subthalamic nucleus (STN) within the basal ganglia is a main clinical target, but the physiological mechanisms of therapeutic STN DBS at the cellular and network level are unclear. We set out to begin to address the hypothesis that a mixture of responses in the basal ganglia output nuclei, combining regularized firing and inhibition, is a key contributor to the effectiveness of STN DBS. We used our computational model of the complete basal ganglia circuit to show how such a mixture of responses in basal ganglia output naturally arises from the network effects of STN DBS. We replicated the diversification of responses recorded in a primate STN DBS study to show that the model's predicted mixture of responses is consistent with therapeutic STN DBS. We then showed how this 'mixture of response' perspective suggests new ideas for DBS mechanisms: first, that the therapeutic frequency of STN DBS is above 100 Hz because the diversification of responses exhibits a step change above this frequency; and second, that optogenetic models of direct STN stimulation during DBS have proven therapeutically ineffective because they do not replicate the mixture of basal ganglia output responses evoked by electrical DBS.     

Deep brain stimulation for Parkinson's disease dissociates mood and motor circuits: a functional MRI case study.

Behavioral disturbances have been reported with subthalamic (STN) deep brain stimulation (DBS) treatment in Parkinson's disease (PD). We report correlative functional imaging (fMRI) of mood and motor responses induced by successive right and left DBS. A 36-year-old woman with medically refractory PD and a history of clinically remitted depression underwent uncomplicated implantation of bilateral STN DBS. High-frequency stimulation of the left electrode improved motor symptoms. Unexpectedly, right DBS alone elicited several reproducible episodes of acute depressive dysphoria. Structural and functional magnetic resonance imaging (fMRI) imaging was carried out with sequential individual electrode stimulation. The electrode on the left was within the inferior STN, whereas the right electrode was marginally superior and lateral to the intended STN target within the Fields of Forel/zona incerta. fMRI image analysis (Analysis of Functional NeuroImages, AFNI) contrasting OFF versus ON stimulation identified significant lateralized blood oxygen level-dependent (BOLD) signal changes with DBS (P < 0.001). Left DBS primarily showed changes in motor regions: increases in premotor and motor cortex, ventrolateral thalamus, putamen, and cerebellum as well as decreases in sensorimotor/supplementary motor cortex. Right DBS showed similar but less extensive change in motor regions. More prominent were the unique increases in superior prefrontal cortex, anterior cingulate (Brodmann's area [BA] 24), anterior thalamus, caudate, and brainstem, and marked widespread decreases in medial prefrontal cortex (BA 9/10). The mood disturbance resolved spontaneously in 4 weeks despite identical stimulation parameters. Transient depressive mood induced by subcortical DBS stimulation was correlated with changes in mesolimbic cortical structures. This case provides new evidence supporting cortical segregation of motor and nonmotor cortico-basal ganglionic systems that may converge in close proximity at the level of the STN and the adjacent white matter tracts (Fields of Forel/zona incerta).     

Deep brain stimulation creates an informational lesion of the stimulated nucleus

Deep brain stimulation (DBS) is an effective treatment for movement disorders, but the mechanisms are unclear. DBS generates inhibition of neurons surrounding the electrode while simultaneously activating the output axons of local neurons. This dual effect does not explain two hallmarks of DBS effectiveness: symptom relief is dependent on using a sufficiently high-stimulation frequency, and clinical effects are analogous to those produced by lesion. The effect of DBS at different frequencies on the output of intrinsically active neurons was studied using computational models. DBS produced frequency-dependent modulation of the variability of neuronal output, and above a critical frequency stimulation resulted in regular output with zero variance. The resulting loss of information offers an explanation for the two hallmarks of DBS effectiveness.     

Current-controlled deep brain stimulation reduces in vivo voltage fluctuations observed during voltage-controlled stimulation

Objective

Clinical deep brain stimulation (DBS) systems typically utilize voltage-controlled stimulation and thus the voltage distribution generated in the brain can be affected by electrode impedance fluctuations. The goal of this study was to experimentally evaluate the theoretical advantages of using current-controlled pulse generators for DBS applications.

Methods

Time-dependent changes in the voltage distribution generated in the brain during voltage-controlled and current-controlled DBS were monitored with in vivo experimental recordings performed in non-human primates implanted with scaled-down clinical DBS electrodes.

Results

In the days following DBS lead implantation, electrode impedance progressively increased. Application of continuous stimulation through the DBS electrode produced a decrease in the electrode impedance in a time dependent manner, with the largest changes occurring within the first hour of stimulation. Over that time period, voltage-controlled stimuli exhibited an increase in the voltage magnitudes generated in the tissue near the DBS electrode, while current-controlled DBS showed minimal changes.

Conclusion

Large electrode impedance changes occur during DBS. During voltage-controlled stimulation, these impedance changes were significantly correlated with changes in the voltage distribution generated in the brain. However, these effects can be minimized with current-controlled stimulation.

Significance

The use of current-controlled DBS may help minimize time-dependent changes in therapeutic efficacy that can complicate patient programming when using voltage-controlled DBS.     

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.

     

Deep brain stimulation for treatment-resistant depression: Efficacy, safety and mechanisms of action

Deep brain stimulation (DBS), a neuromodulation therapy that has been used successfully in the treatment of symptoms associated with movement disorders, has recently undergone clinical trials for individuals suffering from treatment-resistant depression (TRD). Although the small patient numbers and open label study design limit our ability to identify optimum targets and make definitive conclusions about treatment efficacy, a review of the published research demonstrates significant reductions in depressive symptomatology and high rates of remission in a severely treatment-resistant patient group. Despite these encouraging results, an incomplete understanding of the mechanisms of action underlying the therapeutic effects of DBS for TRD is highlighted, paralleling the incomplete understanding of the neuroanatomy of mood regulation and treatment resistance. Proposed mechanisms of action include short and long-term local effects of stimulation at the neuronal level, to modulation of neural network activity.     

Cortical magnetoencephalography of deep brain stimulation for the treatment of postural tremor

The effects of deep brain stimulation (DBS) on motor cortex circuitry in Essential tremor (ET) and Parkinson’s disease (PD) patients are not well understood, in part, because most imaging modalities have difficulty capturing and localizing motor cortex dynamics on the same temporal scale as motor symptom expression. Here, we report on the use of magnetoencephalography (MEG) to characterize sources of postural tremor activity within the brain of an ET/PD patient and the effects of bilateral subthalamic nucleus DBS on these sources. Recordings were performed during unilateral and bilateral DBS at stimulation amplitudes of 0 V, 1 V, and 3 V corresponding to no therapy, subtherapeutic, and therapeutic configurations, respectively. Dipole source localization in reference to the postural tremor frequency recorded with electromyography (EMG) showed prominent sources in both right and left motor cortices when no therapy was provided. These sources dissipated as the amplitude of stimulation increased to a therapeutic level (P = 0.0062). Coherence peaks between the EMG and MEG recordings were seen at both 4 Hz, postural tremor frequency, and at 8 Hz, twice the tremor frequency, with no therapy. Both peaks were reduced with therapeutic DBS. These results demonstrate the capabilities of MEG to record cortical dynamics of tremor during deep brain stimulation and suggest that MEG could be used to examine DBS in the context of motor symptoms of PD and of ET.     

Deep brain stimulation exacerbates hypokinetic dysarthria in a rat model of Parkinson's disease

Motor symptoms of Parkinson's disease (PD) follow the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Deep brain stimulation (DBS) treats some parkinsonian symptoms, such as tremor, rigidity, and bradykinesia, but may worsen certain medial motor symptoms, including hypokinetic dysarthria. The mechanisms by which DBS exacerbates dysarthria while improving other symptoms are unclear and difficult to study in human patients. This study proposes an animal model of DBS‐exacerbated dysarthria. We use the unilateral, 6‐hydroxydopamine (6‐OHDA) rat model of PD to test the hypothesis that DBS exacerbates quantifiable aspects of vocalization. Mating calls were recorded from sexually experienced male rats under healthy and parkinsonian conditions and during DBS of the subthalamic nucleus. Relative to healthy rats, parkinsonian animals made fewer calls with shorter and less complex vocalizations. In the parkinsonian rats, putatively therapeutic DBS further reduced call frequency, duration, and complexity. The individual utterances of parkinsonian rats spanned a greater bandwidth than those of healthy rats, potentially reducing the effectiveness of the vocal signal. This utterance bandwidth was further increased by DBS. We propose that the parkinsonism‐associated changes in call frequency, duration, complexity, and dynamic range combine to constitute a rat analog of parkinsonian dysarthria. Because DBS exacerbates the parkinsonism‐associated changes in each of these metrics, the subthalamic stimulated 6‐OHDA rat is a good model of DBS‐induced hypokinetic dysarthria in PD. This model will help researchers examine how DBS alleviates many motor symptoms of PD while exacerbating parkinsonian speech deficits that can greatly diminish patient quality of life. © 2015 Wiley Periodicals, Inc.