Resting state fMRI reveals increased subthalamic nucleus-motor cortex connectivity in Parkinson's disease

Parkinson's disease (PD) is associated with abnormal hypersynchronicity in basal ganglia-thalamo-cortical loops. The clinical effectiveness of subthalamic nucleus (STN) high frequency stimulation indicates a crucial role of this nucleus within the affected motor networks in PD. Here we investigate alterations in the functional connectivity (FC) profile of the STN using resting state BOLD correlations on a voxel-by-voxel basis in functional magnetic resonance imaging (fMRI). We compared early stage PD patients (n=31) during the medication-off state with healthy controls (n=44). The analysis revealed increased FC between the STN and cortical motor areas (BA 4 and 6) in PD patients in accordance with electrophysiological studies. Moreover, FC analysis of the primary motor cortex (M1) hand area revealed that the FC increase was primarily found in the STN area within the basal ganglia. These findings are in good agreement with recent experimental data, suggesting that an increased STN-motor cortex synchronicity mediated via the so called hyperdirect motor cortex-subthalamic pathway might play a fundamental role in the pathophysiology of PD. An additional subgroup analysis was performed according to the presence (n=16) or absence (n=15) of tremor in patients. Compared to healthy controls tremor patients showed increased STN FC specifically in the hand area of M1 and the primary sensory cortex. In non-tremor patients, increased FC values were also found between the STN and midline cortical motor areas including the SMA. Taken together our results underline the importance of the STN as a key node for the modulation of BG-cortical motor network activity in PD patients.     

深部脑电刺激治疗帕金森病的FDGPET研究

目的研究双侧丘脑底核慢性电刺激术对晚期帕金森病患者脑局部糖代谢的影响及作用机制.方法对7例进行双侧STN DBS的晚期帕金森病患者,在术前和术后1个月电刺激条件下,分别进行18F-脱氧葡萄糖(18F-FDG)PET显像和UPDRS评分,通过SPM进行数据分析.结果 7例患者临床症状明显改善,同时FDG PET显像提示双侧豆状核、脑干、顶枕部、运动前区(BA6)及扣带回的脑代谢增加,而前额叶底部及海马的脑代谢减少(P<0.05).结论双侧STN DBS可使PD患者临床症状改善.FDG PET可作为PD进行STN治疗适应证选择的方法之一.     

Distinct oscillatory STN-cortical loops revealed by simultaneous MEG and local field potential recordings in patients with Parkinson's disease

Neuronal oscillations are assumed to play a pivotal role in the pathophysiology of Parkinson's disease (PD). Neurons in the subthalamic nucleus (STN) generate oscillations which are coupled to rhythmic population activity both in other basal ganglia nuclei and cortical areas. In order to localize these cortical areas, we recorded local field potentials (LFPs) and magnetoencephalography (MEG) simultaneously in PD patients undergoing surgery for deep brain stimulation (DBS). Patients were withdrawn from antiparkinsonian medication and recorded at rest. We scanned the entire brain for oscillations coherent with LFPs recorded from the STN with a frequency domain beamformer. Coherent activity in the low (12-20 Hz) and high (20-35 Hz) beta range was found in the ipsilateral sensorimotor and the premotor cortex. Coherence in the alpha range (7-12 Hz) was observed at various locations in the ipsilateral temporal lobe. In a subset of subjects, the superior temporal gyrus consistently showed coherent alpha oscillations. Our findings provide new insights into patterns of frequency-specific functional connectivity between basal ganglia and cortex and suggest that simultaneous inter-regional interactions may be segregated in the frequency domain. Furthermore, they demonstrate that simultaneous MEG-LFP recordings are a powerful tool to study interactions between brain areas in PD patients undergoing surgery for DBS.     

Topography of cortical and subcortical connections of the human pedunculopontine and subthalamic nuclei

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most common surgical therapy for Parkinson' s disease (PD). DBS of the pedunculopontine nucleus (PPN) is emerging as a promising surgical therapy for PD as well. In order to better characterize these nuclei in humans, we determined the anatomical connections of the PPN and STN and the topography of these connections using probabilistic diffusion tractography. Diffusion tractography was carried out in eight healthy adult subjects using diffusion data acquired at 1.5 T MRI (60 directions, b=1000 s/mm(2), 2 x 2 x 2 mm(3) voxels). The major connections that we identified from single seed voxels within STN or PPN were present in at least half the subjects and the topography of these connections within a 36-voxel region surrounding the initial seed voxel was then examined. Both the PPN and STN showed connections with the cortex, basal ganglia, cerebellum, and down the spinal cord, largely matching connections demonstrated in primates. The topography of motor and associative brain areas in the human STN was strikingly similar to that shown in animals. PPN Topography has not been extensively demonstrated in animals, but we showed significant topography of cortical and subcortical connections in the human PPN. In addition to demonstrating the usefulness of PDT in determining the connections and topography of small grey matter structures in vivo, these results allow for inference of optimal DBS target locations and add to our understanding of the role of these nuclei in PD.     

Indication of surgical therapy for Parkinson's disease

We review the current status of surgical treatment of Parkinson's disease (PD). The advantages of deep brain stimulation (DBS) over ablative surgery include reversibility and controllability of stimulation. In addition, DBS carries a smaller risk of side effects, especially when employed bilaterally. DBS of the thalamus is useful to control tremor which is unresponsive to medication. DBS of the globus pallidus internus (GPi) or the subthalamic nucleus (STN) is useful to control wearing off of motor symptoms which is difficult to manage with medication alone. DBS of STN and GPi improves motor function mainly during the off-period. DBS of STN attenuates levodopa-induced dyskinesia through reduction of dopa requirement, whereas DBS of GPi attenuates dopa-induced dyskinesia directly. DBS of STN is also useful to control symptoms of PD in patients who are intolerant to dopa. However, DBS of either STN or GPi cannot reverse advanced symptoms of PD, which are unresponsive to dopa.     

Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits

Parkinson’s disease (PD) is the most prevalent hypokinetic movement disorder, and symptomatic PD pathogenesis has been ascribed to imbalances between the direct and indirect pathways in the basal ganglia circuitry. Here, we applied glutamate receptor blockers to the subthalamic nucleus (STN) of parkinsonian rats and evaluated locomotor behaviors via single-unit and local-field recordings. Using this model, we found that inhibition of NMDAergic cortico-subthalamic transmission ameliorates parkinsonian motor deficits without eliciting any vivid turning behavior and abolishes electrophysiological abnormalities, including excessive subthalamic bursts, cortico-subthalamic synchronization, and in situ beta synchronization in both the motor cortex and STN. Premotor cortex stimulation revealed that cortico-subthalamic transmission is deranged in PD and directly responsible for the excessive stimulation-dependent bursts and time-locked spikes in the STN, explaining the genesis of PD-associated pathological bursts and synchronization, respectively. Moreover, application of a dopaminergic agent via a microinfusion cannula localized the therapeutic effect to the STN, without correcting striatal dopamine deficiency. Finally, optogenetic overactivation and synchronization of cortico-subthalamic transmission alone sufficiently and instantaneously induced parkinsonian-associated locomotor dysfunction in normal mice. In addition to the classic theory emphasizing the direct-indirect pathways, our data suggest that deranged cortico-subthalamic transmission via the NMDA receptor also plays a central role in the pathophysiology of parkinsonian motor deficits.     

Deep brain stimulation for advanced Parkinson's disease

Deep brain stimulation (DBS) is a new and promising technique for the treatment of movement disorders. Medically intractable Parkinson's disease (PD) is one of the most common indications for DBS. There are three possible subcortical targets for PD, depending on the symptomatology (i.e., the motor subdivision of the thalamus, the globus pallidus internus, the subthalamic nucleus [STN]). Thalamic stimulation has been well established as a safe and effective treatment for essential tremor and the tremor associated with PD. Globus pallidus internus and STN DBS are being investigated for the treatment of all the cardinal signs of PD. This article describes the pathophysiology of PD, the surgical treatment history of PD, surgical techniques used for DBS implants, and the role the perioperative nurse has in the care of the patients undergoing these procedures.     

Network modulation by the subthalamic nucleus in the treatment of Parkinson's disease

Deep brain stimulation of the subthalamic nucleus (STN DBS) has become an accepted tool for the treatment of Parkinson's disease (PD). Although the precise mechanism of action of this intervention is unknown, its effectiveness has been attributed to the modulation of pathological network activity. We examined this notion using positron emission tomography (PET) to quantify stimulation-induced changes in the expression of a PD-related covariance pattern (PDRP) of regional metabolism. These metabolic changes were also compared with those observed in a similar cohort of patients undergoing STN lesioning. We found that PDRP activity declined significantly (P < 0.02) with STN stimulation. The degree of network modulation with DBS did not differ from that measured following lesioning (P = 0.58). Statistical parametric mapping (SPM) revealed that metabolic reductions in the internal globus pallidus (GPi) and caudal midbrain were common to both STN interventions (P < 0.01), although declines in GPi were more pronounced with lesion. By contrast, elevations in posterior parietal metabolism were common to the two procedures, albeit more pronounced with stimulation. These findings indicate that suppression of abnormal network activity is a feature of both STN stimulation and lesioning. Nonetheless, these two interventions may differ metabolically at a regional level.     

Modulation of subthalamic T-type Ca(2+) channels remedies locomotor deficits in a rat model of Parkinson disease

An increase in neuronal burst activities in the subthalamic nucleus (STN) is a well-documented electrophysiological feature of Parkinson disease (PD). However, the causal relationship between subthalamic bursts and PD symptoms and the ionic mechanisms underlying the bursts remain to be established. Here, we have shown that T-type Ca(2+) channels are necessary for subthalamic burst firing and that pharmacological blockade of T-type Ca(2+) channels reduces motor deficits in a rat model of PD. Ni(2+), mibefradil, NNC 55-0396, and efonidipine, which inhibited T-type Ca(2+) currents in acutely dissociated STN neurons, but not Cd(2+) and nifedipine, which preferentially inhibited L-type or the other non–T-type Ca(2+) currents, effectively diminished burst activity in STN slices. Topical administration of inhibitors of T-type Ca(2+) channels decreased in vivo STN burst activity and dramatically reduced the locomotor deficits in a rat model of PD. Cd(2+) and nifedipine showed no such electrophysiological and behavioral effects. While low-frequency deep brain stimulation (DBS) has been considered ineffective in PD, we found that lengthening the duration of the low-frequency depolarizing pulse effectively improved behavioral measures of locomotion in the rat model of PD, presumably by decreasing the availability of T-type Ca(2+) channels. We therefore conclude that modulation of subthalamic T-type Ca(2+) currents and consequent burst discharges may provide new strategies for the treatment of PD.     

Deep brain stimulation: how does it work?

Deep brain stimulation has significantly improved the motor symptoms in patients with Parkinson's disease (PD) and other movement disorders. The mechanisms responsible for these improvements continue to be explored. Inhibition at the site of stimulation has been the prevailing explanation for the symptom improvement observed with deep brain stimulation. Research using microelectrode recording during deep brain stimulation in the MPTP monkey model of PD has helped clarify how electrical stimulation of structures within the basal ganglia-thalamocortical circuit improves motor symptoms, and suggests that activation of output and the resultant change in pattern of neuronal activity that permeates throughout the basal ganglia motor circuit is the mechanism responsible for symptom improvement.     

Metabolic brain networks associated with cognitive function in Parkinson's disease

The motor manifestations of Parkinson's disease (PD) have been linked to an abnormal spatial covariance pattern involving basal ganglia thalamocortical pathways. By contrast, little is known about the functional networks that underlie cognitive dysfunction in this disorder. To identify such patterns, we studied 15 non-demented PD patients using FDG PET and a voxel-based network modeling approach. We detected a significant covariance pattern that correlated (p<0.01) with performance on tests of memory and executive functioning. This PD-related cognitive pattern (PDCP) was characterized by metabolic reductions in frontal and parietal association areas and relative increases in the cerebellar vermis and dentate nuclei. To validate this pattern, we analyzed data from 32 subsequent PD patients of similar age, disease duration and severity. Prospective measurements of PDCP activity predicted memory performance (p<0.005), visuospatial function (p<0.01), and perceptual motor speed (p<0.005) in this validation sample. PDCP scores additionally exhibited an excellent degree of test-retest reliability (intraclass correlation coefficient, ICC=0.89) in patients undergoing repeat FDG PET at an 8-week interval. Unlike the PD-related motor pattern, PDCP expression was not significantly altered by antiparkinsonian treatment with either intravenous levodopa or deep brain stimulation (DBS). These findings substantiate the PDCP as a reproducible imaging marker of cognitive function in PD. Because PDCP expression is not altered by routine antiparkinsonian treatment, this measure of network activity may prove useful in clinical trials targeting the progression of non-motor manifestations of this disorder.     

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.     

Free-living energy expenditure reduced after deep brain stimulation surgery for Parkinson's disease

Background: The clinical picture in Parkinson’s disease (PD) is characterized by bradykinesia, rigidity, resting tremor and postural instability. In advanced stages of the disease, many patients will experience reduced efficacy of medication with fluctuations in symptoms and dyskinesias. Surgical treatment with deep brain stimulation in the subthalamic nucleus (STN‐DBS) is now considered the gold standard in fluctuating PD. Many patients experience a gain of weight following the surgery. The aim of this study was to identify possible mechanisms, which may contribute to body weight gain in patients with PD following bilateral STN‐DBS surgery. Methods: Ten patients with PD were studied before bilateral STN‐DBS surgery, and seven patients were studied again 3 and 12 months postoperatively. Clinical examination and resting metabolic rate with and without medical treatment was measured before and after STN‐DBS. Furthermore, free‐living energy expenditure, body composition, energy intake, peak oxygen consumption, maximal workload and leisure time physical activity were measured before and 3 and 12 months after surgery. Results: The STN‐DBS operated patients had a significant weight gain of 4·7 ± 1·6 kg (mean ± SE) 12 months postoperatively, and the weight gain was in the fat mass. The free‐living energy expenditure decreased postoperatively 13 ± 4% even though the reported dietary intake was reduced. A decreased energy expenditure took place in the non‐resting energy expenditure. The reported daily leisure time activity, peak oxygen consumption and maximal workload were unchanged. Conclusion: The STN‐DBS operated patients have a significant postoperative weight gain, as a result of a decrease in free‐living energy expenditure concomitant with an insufficient decrease in energy intake.     

Role of hyperactive cerebellum and motor cortex in Parkinson's disease

Previous neuroimaging studies have found hyperactivation in the cerebellum and motor cortex and hypoactivation in the basal ganglia in patients with Parkinson's disease (PD) but the relationship between the two has not been established. This study examined whether cerebellar and motor cortex hyperactivation is a compensatory mechanism for hypoactivation in the basal ganglia or is a pathophysiological response that is related to the signs of the disease. Using a BOLD contrast fMRI paradigm PD patients and healthy controls performed automatic and cognitively controlled thumb pressing movements. Regions of interest analysis quantified the BOLD activation in motor areas, and correlations between the hyperactive and hypoactive regions were performed, along with correlations between the severity of upper limb rigidity and BOLD activation. There were three main findings. First, the putamen, supplementary motor area (SMA) and pre-SMA were hypoactive in PD patients. The left and right cerebellum and the contralateral motor cortex were hyperactive in PD patients. Second, PD patients had a significant negative correlation between the BOLD activation in the ipsilateral cerebellum and the contralateral putamen. The correlation between the putamen and motor cortex was not significant. Third, the BOLD activation in the motor cortex was positively correlated with the severity of upper limb rigidity, but the BOLD activation in the cerebellum was not correlated with rigidity. Further, the activation in the motor cortex was not correlated with upper extremity bradykinesia. These findings provide new evidence supporting the hypothesis that hyperactivation in the ipsilateral cerebellum is a compensatory mechanism for the defective basal ganglia. Our findings also provide the first evidence from neuroimaging that hyperactivation in the contralateral primary motor cortex is not a compensatory response but is directly related to upper limb rigidity.     

Subthalamic GAD gene transfer in Parkinson disease patients who are candidates for deep brain stimulation

This gene transfer experiment is the first Parkinson's Disease (PD) protocol to be submitted to the Recombinant DNA Advisory Committee. The principal investigators have uniquely focused their careers on both pre-clinical work on gene transfer in the brain and clinical expertise in management and surgical treatment of patients with PD. They have extensively used rodent models of PD for proof-of-principle experiments on the utility of different vector systems. PD is an excellent target for gene therapy, because it is a complex acquired disease of unknown etiology (apart from some rare familial cases) yet it is characterized by a specific neuroanatomical pathology, the degeneration of dopamine neurons of the substantia nigra (SN) with loss of dopamine input to the striatum. This pathology results in focal changes in the function of several deep brain nuclei, which have been well-characterized in humans and animal models and which account for many of the motor symptoms of PD. Our original approaches, largely to validate in vivo gene transfer in the brain, were designed to facilitate dopamine transmission in the striatum using an AAV vector expressing dopamine-synthetic enzymes. Although these confirmed the safety and potential efficacy of AAV, complex patient responses to dopamine augmenting medication as well as poor results and complications of human transplant studies suggested that this would be a difficult and potentially dangerous clinical strategy using current approaches. Subsequently, we and others investigated the use of growth factors, including GDNF. These showed some encouraging effects on dopamine neuron survival and regeneration in both rodent and primate models; however, uncertain consequences of long-term growth factor expression and question regarding timing of therapy in the disease course must be resolved before any clinical study can be contemplated. We now propose to infuse into the subthalamic nucleus (STN) recombinant AAV vectors expressing the two isoforms of the enzyme glutamic acid decarboxylase (GAD-65 and GAD-67), which synthesizes the major inhibitory neurotransmitter in the brain, GABA. The STN is a very small nucleus (140 cubic mm or 0.02% of the total brain volume, consisting of approximately 300,000 neurons) which is disinhibited in PD, leading to pathological excitation of its targets, the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNpr). Increased GPi/SNpr outflow is believed responsible for many of the cardinal symptoms of PD, i.e., tremor, rigidity, bradykinesia, and gait disturbance. A large amount of data based on lesioning, electrical stimulation, and local drug infusion studies with GABA-agonists in human PD patients have reinforced this circuit model of PD and the central role of the STN. Moreover, the closest conventional surgical intervention to our proposal, deep brain stimulation (DBS) of the STN, has shown remarkable efficacy in even late stage PD, unlike the early failures associated with recombinant GDNF infusion or cell transplantation approaches in PD. We believe that our gene transfer strategy will not only palliate symptoms by inhibiting STN activity, as with DBS, but we also have evidence that the vector converts excitatory STN projections to inhibitory projections. This additional dampening of outflow GPi/SNpr outflow may provide an additional advantage over DBS. Moreover, of perhaps the greatest interest, our preclinical data suggests that this strategy may also be neuroprotective, so this therapy may slow the degeneration of dopaminergic neurons. We will use both GAD isoforms since both are typically expressed in inhibitory neurons in the brain, and our data suggest that the combination of both isoforms is likely to be most beneficial. Our preclinical data includes three model systems: (1) old, chronically lesioned parkinsonian rats in which intraSTN GAD gene transfer results not only in improvement in both drug-induced asymmetrical behavior (apomorphine symmetrical rotations), but also in spontaneous behaviors. In our second model, GAD gene transfer precedes the generation of a dopamine lesion. Here GAD gene transfer showed remarkable neuroprotection. Finally, we carried out a study where GAD-65 and GAD-67 were used separately in monkeys that were resistant to MPTP lesioning and hence showed minimal symptomatology. Nevertheless GAD gene transfer showed no adverse effects and small improvements in both Parkinson rating scales and activity measures were obtained. In the proposed clinical trial, all patients will have met criteria for and will have given consent for STN DBS elective surgery. Twenty patients will all receive DBS electrodes, but in addition they will be randomized into two groups, to receive either a solution containing rAAV-GAD, or a solution which consists just of the vector vehicle, physiological saline. Patients, care providers, and physicians will be blind as to which solution any one patient receives. All patients, regardless of group, will agree to not have the DBS activated until the completion and unblinding of the study. Patients will be assessed with a core clinical assessment program modeled on the CAPSIT, and in addition will also undergo a preop and several postop PET scans. At the conclusion of the study, if any patient with sufficient symptomatic improvement will be offered DBS removal if they so desire. Any patients with no benefit will simply have their stimulators activated, which would normally be appropriate therapy for them and which requires no additional operations. If any unforeseen symptoms occur from STN production of GABA, this might be controlled by blocking STN GABA release with DBS, or STN lesioning could be performed using the DBS electrode. Again, this treatment would not subject the patient to additional invasive brain surgery. The trial described here reflects an evolution in our thinking about the best strategy to make a positive impact in Parkinson Disease by minimizing risk and maximizing potential benefit. To our knowledge, this proposal represents the first truly blinded, completely controlled gene or cell therapy study in the brain, which still provides the patient with the same surgical procedure which they would normally receive and should not subject the patient to additional surgical procedures regardless of the success or failure of the study. This study first and foremost aims to maximally serve the safety interests of the individual patient while simultaneously serving the public interest in rigorously determining in a scientific fashion if gene therapy can be effective to any degree in treating Parkinson's disease.     

Speech motor program maintenance,but not switching,is enhanced by left-hemispheric deep brain stimulation in Parkinson's disease

Speech reaction time (SRT) was measured in a response priming protocol in 12 participants with Parkinson's disease (PD) and hypokinetic dysarthria “on” and “off” left-hemispheric deep brain stimulation (DBS). Speech preparation was measured during speech motor programming in two randomly ordered speech conditions: speech maintenance and switching. Double blind testing was completed in participants with DBS of globus pallidus pars interna (GPi) (n?=?5) or subthalamic nucleus (STN) (n?=?7). SRT was significantly faster in the maintenance vs switch task, regardless of DBS state. SRT was faster in the speech maintenance task “on” stimulation, while there was no difference in speech switching “on” and “off” DBS. These data suggest that left-hemispheric DBS may have differential effects on aspects of speech preparation in PD. It is hypothesized that speech maintenance improvements may result from DBS-induced cortical enhancements, while the lack of difference in switching may be related to inhibition deficits mediated by the right-hemisphere. Alternatively, DBS may have little influence on the higher level motor processes (i.e., motor planning) which it is believed the switch task engaged to a greater extent than the maintenance task.     

Patient-specific analysis of the relationship between the volume of tissue activated during DBS and verbal fluency

Deep brain stimulation (DBS) for the treatment of advanced Parkinson's disease involves implantation of a lead with four small contacts usually within the subthalamic nucleus (STN) or globus pallidus internus (GPi). While generally safe from a cognitive standpoint, STN DBS has been commonly associated with a decrease in the speeded production of words, a skill referred to as verbal fluency. Virtually all studies comparing presurgical to postsurgical verbal fluency performance have detected a decrease with DBS. The decline may be attributable in part to the surgical procedures, yet the relative contributions of stimulation effects are not known. In the present study, we used patient-specific DBS computer models to investigate the effects of stimulation on verbal fluency performance. Specifically, we investigated relationships of the volume and locus of activated STN tissue to verbal fluency outcome. Stimulation of different electrode contacts within the STN did not affect total verbal fluency scores. However, models of activation revealed subtle relationships between the locus and volume of activated tissue and verbal fluency performance. At ventral contacts, more tissue activation inside the STN was associated with decreased letter fluency performance. At optimal contacts, more tissue activation within the STN was associated with improved letter fluency performance. These findings suggest subtle effects of stimulation on verbal fluency performance, consistent with the functional nonmotor subregions/somatotopy of the STN.     

Probabilistic analysis of activation volumes generated during deep brain stimulation

Deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson's disease (PD) and shows great promise for the treatment of several other disorders. However, while the clinical analysis of DBS has received great attention, a relative paucity of quantitative techniques exists to define the optimal surgical target and most effective stimulation protocol for a given disorder. In this study we describe a methodology that represents an evolutionary addition to the concept of a probabilistic brain atlas, which we call a probabilistic stimulation atlas (PSA). We outline steps to combine quantitative clinical outcome measures with advanced computational models of DBS to identify regions where stimulation-induced activation could provide the best therapeutic improvement on a per-symptom basis. While this methodology is relevant to any form of DBS, we present example results from subthalamic nucleus (STN) DBS for PD. We constructed patient-specific computer models of the volume of tissue activated (VTA) for 163 different stimulation parameter settings which were tested in six patients. We then assigned clinical outcome scores to each VTA and compiled all of the VTAs into a PSA to identify stimulation-induced activation targets that maximized therapeutic response with minimal side effects. The results suggest that selection of both electrode placement and clinical stimulation parameter settings could be tailored to the patient's primary symptoms using patient-specific models and PSAs.     

High frequency rTMS modulation of the sensorimotor networks: behavioral changes and fMRI correlates

Repetitive transcranial magnetic stimulation (rTMS) to the primary motor cortex (M1) may induce functional modulation of motor performance and sensory perception. To address the underlying neurophysiological modulation following 10 Hz rTMS applied over M1, we examined cortical activation using 3T functional magnetic resonance imaging (fMRI), as well as the associated motor and sensory behavioral changes. The motor performance measure involved a sequential finger motor task that was also used as an activation task during fMRI. For sensory assessment, current perception threshold was measured before and after rTMS outside the MR scanner, and noxious mechanical stimulation was used as an activation task during fMRI. We found that significant activation in the bilateral basal ganglia, left superior frontal gyrus, bilateral pre-SMA, right medial temporal lobe, right inferior parietal lobe, and right cerebellar hemisphere correlated with enhanced motor performance in subjects that received real rTMS compared with sham-stimulated controls. Conversely, significant deactivation in the right superior and middle frontal gyri, bilateral postcentral and bilateral cingulate gyri, left SMA, right insula, right basal ganglia, and right cerebellar hemisphere were associated with an increase in the sensory threshold. Our findings reveal that rTMS induced rapid changes in the sensorimotor networks associated with sensory perception and motor performance and demonstrate the complexity of such intervention.     

Thalamic stimulation for parkinsonian tremor: correlation between regional cerebral blood flow and physiological tremor characteristics

We used (15)O-labeled water (H(2)(15)O) positron emission tomography (PET) to study eight Parkinson's disease (PD) patients with unilateral ventral intermediate (Vim) thalamic nucleus deep brain stimulation (DBS) for severe tremor. Triaxial accelerometry (TRIAX) was used during imaging to obtain on-line measures of tremor characteristics. Regional cerebral blood flow (rCBF) scans together with TRIAX recordings were collected in three stimulation conditions (OFF, MID, and ON, corresponding, respectively, to 0%, 50%, and 100% reductions in mean accelerometry signal). Statistical Parametric Mapping (SPM99) revealed significant rCBF reductions during stimulation in the ipsilateral sensorimotor cortex (SMC) and the contralateral cerebellum, as well as concurrent increases in the ipsilateral ventral thalamus (P < 0.05, corrected). Covariate analysis of rCBF with physiological tremor characteristics revealed that tremor acceleration correlated positively with changes in the SMC and supplementary motor cortex ipsilaterally (P < 0.05, uncorrected), and negatively with changes in the ipsilateral cuneus (P < 0.05, corrected). After removing tremor acceleration effects, changes in tremor frequency correlated negatively with changes in the contralateral dentate nucleus and pons (P < 0.05, uncorrected). Our results suggest that Vim DBS for PD tremor modulates the activity of cerebello-thalamo-cortical pathways. Specific tremor characteristics relate to activity in different nodes of this system.