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1.  Electrode Position and Current Amplitude Modulate Impulsivity after Subthalamic Stimulation in Parkinsons Disease—A Computational Study 
Background: Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) is highly effective in alleviating motor symptoms of Parkinson's disease (PD) which are not optimally controlled by dopamine replacement therapy. Clinical studies and reports suggest that STN-DBS may result in increased impulsivity and de novo impulse control disorders (ICD).
Objective/Hypothesis: We aimed to compare performance on a decision making task, the Iowa Gambling Task (IGT), in healthy conditions (HC), untreated and medically-treated PD conditions with and without STN stimulation. We hypothesized that the position of electrode and stimulation current modulate impulsivity after STN-DBS.
Methods: We built a computational spiking network model of basal ganglia (BG) and compared the model's STN output with STN activity in PD. Reinforcement learning methodology was applied to simulate IGT performance under various conditions of dopaminergic and STN stimulation where IGT total and bin scores were compared among various conditions.
Results: The computational model reproduced neural activity observed in normal and PD conditions. Untreated and medically-treated PD conditions had lower total IGT scores (higher impulsivity) compared to HC (P < 0.0001). The electrode position that happens to selectively stimulate the part of the STN corresponding to an advantageous panel on IGT resulted in de-selection of that panel and worsening of performance (P < 0.0001). Supratherapeutic stimulation amplitudes also worsened IGT performance (P < 0.001).
Conclusion(s): In our computational model, STN stimulation led to impulsive decision making in IGT in PD condition. Electrode position and stimulation current influenced impulsivity which may explain the variable effects of STN-DBS reported in patients.
doi:10.3389/fphys.2016.00585
PMCID: PMC5126055  PMID: 27965590
impulsivity; sub thalamic stimulation; Parkinson's disease; Iowa gambling task; reinforcement learning
2.  Mapping Go–No-Go performance within the subthalamic nucleus region 
Brain  2010;133(12):3625-3634.
The basal ganglia are thought to be important in the selection of wanted and the suppression of unwanted motor patterns according to explicit rules (i.e. response inhibition). The subthalamic nucleus has been hypothesized to play a particularly critical role in this function. Deep brain stimulation of the subthalamic nucleus in individuals with Parkinson’s disease has been used to test this hypothesis, but results have been variable. Based on current knowledge of the anatomical organization of the subthalamic nucleus, we propose that the location of the contacts used in deep brain stimulation could explain variability in the effects of deep brain stimulation of the subthalamic nucleus on response inhibition tasks. We hypothesized that stimulation affecting the dorsal subthalamic nucleus (connected to the motor cortex) would be more likely to affect motor symptoms of Parkinson’s disease, and stimulation affecting the ventral subthalamic nucleus (connected to higher order cortical regions) would be more likely to affect performance on a response inhibition task. We recruited 10 individuals with Parkinson’s disease and bilateral deep brain stimulation of the subthalamic nucleus with one contact in the dorsal and another in the ventral subthalamic region on one side of the brain. Patients were tested with a Go–No-Go task and a motor rating scale in three conditions: stimulation off, unilateral dorsal stimulation and unilateral ventral stimulation. Both dorsal and ventral stimulation improved motor symptoms, but only ventral subthalamic stimulation affected Go–No-Go performance, decreasing hits and increasing false alarms, but not altering reaction times. These results suggest that the ventral subthalamic nucleus is involved in the balance between appropriate selection and inhibition of prepotent responses in cognitive paradigms, but that a wide area of the subthalamic nucleus region is involved in the motor symptoms of Parkinson’s disease. This finding has implications for resolving inconsistencies in previous research, highlights the role of the ventral subthalamic nucleus region in response inhibition and suggests an approach for the clinical optimization of deep brain stimulation of the subthalamic nucleus for both motor and cognitive functions.
doi:10.1093/brain/awq256
PMCID: PMC2995882  PMID: 20855421
subthalamic nucleus; deep brain stimulation; response inhibition; Parkinson’s disease
3.  Deep brain stimulation of the subthalamic nucleus: anatomical, neurophysiological, and outcome correlations with the effects of stimulation 
Objectives: Bilateral chronic high frequency stimulation of the subthalamic nucleus (STN), through the stereotactical placement of stimulating electrodes, effectively improves the motor symptoms of severe Parkinson's disease. Intraoperative neurophysiological and clinical monitoring techniques (neuronal electrical activity recording and intraoperative stimulation) may improve and refine the localisation of the nucleus. The objective of this work was to compare the preoperative CT and MRI localisation with the intraoperative neurophysiological identification of STN. The relation between the localisation of the STN and the position of the most effective contact of the permanent quadripolar electrode at a 3 month and 1 year follow up was also studied.
Methods: Fourteen consecutive parkinsonian patients were submitted to bilateral implant for STN stimulation. All the patients underwent a standard MRI and stereotactic CT to obtain, by image fusion and localisation software, the stereotactical coordinates of STN. The STN extension and boundaries were identified by a semimicrorecording of the neuronal electrical activity. The definitive quadripolar electrode was positioned to locate at least two contacts within the STN recording area. Intraoperative macrostimulation was performed to confirm the correct position of the electrode. Postoperative clinical evaluation of the effects of stimulation was checked for each contact of the quadripolar electrode testing the improvement on contralateral rigidity to select the best contact. This evaluation was repeated at 3 months and 1 year after surgery.
Results: In 35.7% of the procedures it was necessary to perform more than one track to get a recording of neuronal activity consistent with STN.
The mean position of the central point of all the 28 STN recording areas in respect of the AC-PC line midpoint was 2.7 mm posterior (SD 0.7), 3.8 mm inferior (SD 1.1), and 11.6 mm lateral (SD 0.9), and the mean distance between the anatomical target and the central point of the STN as defined by intraoperative recording was 0.5 mm (SD 0.5) on the anteroposterior plane, 0.7 mm (SD 0.7) on the lateral plane, and 0.9 mm (SD 0.6) on the vertical plane. At 1 year the mean position of the central point of the most effective contact of the electrode in respect of the AC-PC line midpoint was 1.7 mm posterior (SD 0.9), 1.7 mm inferior (SD 1.5), and 12.3 mm lateral (SD 0.9).
Conclusion: The results highlight the role of the intraoperative recording to get a more accurate localisation of the STN in surgery for Parkinson's disease, allowing the identification of the boundaries and of the extension of the nucleus. The most effective contact of the quadripolar electrode was always in the upper part of the STN recording area or immediately above it, suggesting a role of this region in the clinical effectiveness of the STN electrical stimulation.
doi:10.1136/jnnp.72.1.53
PMCID: PMC1737677  PMID: 11784826
4.  Do Patient's Get Angrier Following STN, GPi, and Thalamic Deep Brain Stimulation 
NeuroImage  2010;54S1:S227-S232.
Objective
The objective of the study was to examine whether deep brain stimulation (DBS) of the subthalamic nucleus (STN), the globus pallidus internus (GPi), and/or the ventralis intermedius thalamic nucleus (Vim) was associated with making patients angrier pre to post-surgical intervention.
Background
Secondary outcome analysis of the NIH COMPARE Parkinson's Disease DBS trial revealed that participants were angrier and had more mood and cognitive side effects following DBS. Additionally blinded on/off analysis did not change anger scores. The sample size was small but suggested that STN DBS may have been worse than GPi in provoking anger. We endeavored to examine this question utilizing a larger dataset (the UF INFORM database), and also we included a third surgical target (Vim) which has been utilized for a different disease, essential tremor.
Methods
Consecutive patients from the University of Florida Movement Disorders Center who were implanted with unilateral DBS for Parkinson's Disease (STN or GPi) or Essential Tremor (Vim) were included. Patients originally implanted at outside institutions were excluded. Pre- and 4-6 month postoperative Visual Analog Mood Scales (VAMS) scores for all three groups were compared; additionally, pre- and 1-3 month scores were compared for STN and GPi patients. A linear regression model was utilized to analyze the relationship between the VAMS anger score and the independent variables of age, years with symptoms, Mini-mental status examination (MMSE) score, handedness, ethnicity, gender, side of surgery, target of surgery, baseline Dementia Rating Scale (DRS) total score, baseline Beck Depression Index (BDI) score, micro and macro electrode passes, and years of education. Levodopa equivalent dosages and dopamine agonist use was analyzed for a potential impact on anger scores.
Results
A total of 322 unilateral DBS procedures were analyzed, with STN (n= 195), Vim (n=71), and GPi (n=56) making up the cohort. An ANOVA analysis was used to detect significant differences among the three targets in the changes pre- to post-operatively. Similar to the COMPARE dataset, at four months the only subscore of VAMS to reveal a significant difference between the three targets was the angry subscore, with GPi revealing a mean (standard) change of 2.38 (9.53), STN 4.82 (14.52), and Vim -1.17 (11.51) (p-value = 0.012). At 1-3 months postop, both STN and GPi groups were significantly angrier (p= 0.004), but there was no significant difference between the two groups. However, GPi patients were significantly more confused as compared to STN patients (p= 0.016). The linear regression model which sought independent explanatory variables revealed a relationship between the VAMS anger score and the surgical target and the disease duration. The mean changes for STN and GPi DBS pre- to post were 11.67 (p= 0.001) and 8.21 (p= 0.022) units more than those with Vim, respectively. For every year added of disease duration, the VAMS anger score increased by 0.24 (p= 0.022). For the GPi and STN groups, number of microelectrode passes was significantly associated with angry score changes (p= 0.014), with the anger score increasing 2.29 units per microelectrode pass. Independent variables not associated with the VAMS anger score included the surgery side, handedness, gender, ethnicity, education, age at surgery, MMSE, DRS, and BDI scores. Although the STN group significantly decreased in LED when compared to GPi, there was no relationship to anger scores. Similarly dopamine agonist use was not different between STN and GPi groups, and did not correlate with the VAMS anger score changes.
Conclusions
STN and GPi DBS for Parkinson's disease were associated with significantly higher anger scores pre- to post-DBS as compared to Vim for essential tremor. Anger score changes in STN and GPi patients seem to be associated with microelectrode passes, suggesting it may be a lesional effect. PD patients with longer disease durations may be particularly susceptible, and this should be kept in mind when discussing the potential of DBS surgery for an individual patient. Essential tremor patients who on average have much longer disease durations did not get angrier. The changes in anger scores were not related to LED change or dopamine agonist use. Whether the induction of anger is disease specific or target specific is not currently known, however our data would suggest that PD patients implanted in STN or GPi are at a potential risk. Finally, on closer inspection of the COMPARE DBS data VAMS anger scores did not change on or off DBS, suggesting that anger changes may be more a lesional effect rather than a stimulation induced one(Okun et al., 2009).
doi:10.1016/j.neuroimage.2010.09.077
PMCID: PMC3014411  PMID: 20932923
Subthalamic nucleus; globus pallidus; ventralis intermedius nucleus; deep brain stimulation; anger; Parkinson's disease; tremor
5.  The Subthalamic Nucleus becomes a Generator of Bursts in the Dopamine-Depleted State. Its High Frequency Stimulation Dramatically Weakens Transmission to the Globus Pallidus 
Excessive burst firing in the dopamine-depleted basal ganglia correlates with severe motor symptoms of Parkinson's disease that are attenuated by high frequency electrical stimulation of the subthalamic nucleus (STN). Here we test the hypothesis that pathological bursts in dopamine-deprived basal ganglia are generated within the STN and transmitted to globus pallidus neurons. To answer this question we recorded excitatory synaptic currents and potentials from subthalamic and pallidal neurons in the basal ganglia slice (BGS) from dopamine-depleted mice while continuously blocking GABAA receptors. In control mice, a single electrical stimulus delivered to the internal capsule or the rostral pole of the STN evoked a short duration, small amplitude, monosynaptic EPSC in subthalamic neurons. In contrast, in the dopamine-depleted BGS, this monosynaptic EPSC was amplified and followed by a burst of polysynaptic EPSCs that eventually reverberated three to seven times, providing a long lasting response that gave rise to bursts of EPSCs and spikes in GP neurons. Repetitive (10–120 Hz) stimulation delivered to the STN in the dopamine-depleted BGS attenuated STN-evoked bursts of EPSCs in pallidal neurons after several minutes of stimulation but only high frequency (90–120 Hz) stimulation replaced them with small amplitude EPSCs at 20 Hz. We propose that the polysynaptic pathway within the STN amplifies subthalamic responses to incoming excitation in the dopamine-depleted basal ganglia, thereby transforming the STN into a burst generator and entraining pallidal neurons in pathogenic bursting activities. High frequency stimulation of the STN prevents the transmission of this pathological activity to globus pallidus and imposes a new glutamatergic synaptic noise on pallidal neurons.
doi:10.3389/fnsys.2011.00043
PMCID: PMC3115486  PMID: 21716635
basal ganglia; subthalamic nucleus; Parkinson; high frequency stimulation; burst firing; basal ganglia slice
6.  Defining a role for the subthalamic nucleus within operative theoretical models of subcortical participation in language 
Objective:To investigate the effects of bilateral, surgically induced functional inhibition of the subthalamic nucleus (STN) on general language, high level linguistic abilities, and semantic processing skills in a group of patients with Parkinson's disease.
Methods:Comprehensive linguistic profiles were obtained up to one month before and three months after bilateral implantation of electrodes in the STN during active deep brain stimulation (DBS) in five subjects with Parkinson's disease (mean age, 63.2 years). Equivalent linguistic profiles were generated over a three month period for a non-surgical control cohort of 16 subjects with Parkinson's disease (NSPD) (mean age, 64.4 years). Education and disease duration were similar in the two groups. Initial assessment and three month follow up performance profiles were compared within subjects by paired t tests. Reliability change indices (RCI), representing clinically significant alterations in performance over time, were calculated for each of the assessment scores achieved by the five STN-DBS cases and the 16 NSPD controls, relative to performance variability within a group of 16 non-neurologically impaired adults (mean age, 61.9 years). Proportions of reliable change were then compared between the STN-DBS and NSPD groups.
Results:Paired comparisons within the STN-DBS group showed prolonged postoperative semantic processing reaction times for a range of word types coded for meanings and meaning relatedness. Case by case analyses of reliable change across language assessments and groups revealed differences in proportions of change over time within the STN-DBS and NSPD groups in the domains of high level linguistics and semantic processing. Specifically, when compared with the NSPD group, the STN-DBS group showed a proportionally significant (p<0.05) reliable improvement in postoperative scores achieved on the word test-revised (TWT-R), as well as a reliable decline (p<0.01) in the accuracy of lexical decisions about words with many meanings and a high degree of relatedness between meanings.
Conclusions:Bilateral STN-DBS affects certain aspects of linguistic functioning, supporting a potential role for the STN in the mediation of language processes.
doi:10.1136/jnnp.74.11.1543
PMCID: PMC1738254  PMID: 14617713
7.  Effects of deep brain stimulation of dorsal versus ventral subthalamic nucleus regions on gait and balance in Parkinson disease 
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor function including gait and stability in people with PD, but differences in DBS contact locations within the STN may contribute to variability in the degree of improvement. Based on anatomic connectivity, dorsal STN may be preferentially involved in motor function and ventral STN in cognitive function. To determine whether dorsal DBS affects gait and balance more than ventral DBS, we conducted a double-blind evaluation of 23 PD patients with bilateral STN DBS. Each participant underwent gait analysis and balance testing off Parkinson medication in three DBS conditions (unilateral DBS in dorsal STN region, unilateral DBS in ventral STN region, and both stimulators off) on one day. For UPDRS-III scores and velocity for Fast and Pref gait, as well as stride length for Fast and Pref gait, dorsal and ventral stimulation improved gait, compared to the off condition (post hoc tests, p<0.05). However, there were no differences with dorsal compared to ventral stimulation. Balance, assessed using a multi-item clinical balance test (mini-BESTest), was similar across conditions. Absence of differences in gait and balance between dorsal and ventral conditions suggests motor connections involved in gait and balance may be more diffusely distributed in STN than previously thought, as opposed to neural connections involved in cognitive processes, such as response inhibition, which are more affected by ventral stimulation.
doi:10.1136/jnnp.2010.232900
PMCID: PMC3250990  PMID: 21478202
Parkinson Disease; Gait; Balance; Deep Brain Stimulation; Subthalamic Nucleus
8.  Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson’s disease 
Brain  2016;139(5):1482-1496.
Oswal et al. characterise the effect of deep brain stimulation (DBS) on STN–cortical synchronisation in Parkinson–s disease. They propose that cortical driving of the STN in beta frequencies is subdivided anatomically and spectrally, corresponding to the hyperdirect and indirect pathways. DBS predominantly suppresses the former.
Oswal et al. characterise the effect of deep brain stimulation (DBS) on STN–cortical synchronisation in Parkinson–s disease. They propose that cortical driving of the STN in beta frequencies is subdivided anatomically and spectrally, corresponding to the hyperdirect and indirect pathways. DBS predominantly suppresses the former.
Chronic dopamine depletion in Parkinson’s disease leads to progressive motor and cognitive impairment, which is associated with the emergence of characteristic patterns of synchronous oscillatory activity within cortico-basal-ganglia circuits. Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson’s disease, but its influence on synchronous activity in cortico-basal-ganglia loops remains to be fully characterized. Here, we demonstrate that deep brain stimulation selectively suppresses certain spatially and spectrally segregated resting state subthalamic nucleus–cortical networks. To this end we used a validated and novel approach for performing simultaneous recordings of the subthalamic nucleus and cortex using magnetoencephalography (during concurrent subthalamic nucleus deep brain stimulation). Our results highlight that clinically effective subthalamic nucleus deep brain stimulation suppresses synchrony locally within the subthalamic nucleus in the low beta oscillatory range and furthermore that the degree of this suppression correlates with clinical motor improvement. Moreover, deep brain stimulation relatively selectively suppressed synchronization of activity between the subthalamic nucleus and mesial premotor regions, including the supplementary motor areas. These mesial premotor regions were predominantly coupled to the subthalamic nucleus in the high beta frequency range, but the degree of deep brain stimulation-associated suppression in their coupling to the subthalamic nucleus was not found to correlate with motor improvement. Beta band coupling between the subthalamic nucleus and lateral motor areas was not influenced by deep brain stimulation. Motor cortical coupling with subthalamic nucleus predominantly involved driving of the subthalamic nucleus, with those drives in the higher beta frequency band having much shorter net delays to subthalamic nucleus than those in the lower beta band. These observations raise the possibility that cortical connectivity with the subthalamic nucleus in the high and low beta bands may reflect coupling mediated predominantly by the hyperdirect and indirect pathways to subthalamic nucleus, respectively, and that subthalamic nucleus deep brain stimulation predominantly suppresses the former. Yet only the change in strength of local subthalamic nucleus oscillations correlates with the degree of improvement during deep brain stimulation, compatible with the current view that a strengthened hyperdirect pathway is a prerequisite for locally generated beta activity but that it is the severity of the latter that may determine or index motor impairment.
doi:10.1093/brain/aww048
PMCID: PMC4845255  PMID: 27017189
deep brain stimulation; Parkinson’s disease; local field potential; resting state networks; magnetoencephalography
9.  Cognition and Mood in Parkinson Disease in STN versus GPi DBS: The COMPARE Trial 
Annals of neurology  2009;65(5):586-595.
Objective
There is a paucity of level-one evidence comparing STN and GPi DBS. Our aim in this prospective blinded randomized trial was to compare the cognitive and mood effects of unilateral subthalamic nucleus (STN) vs. unilateral globus pallidus interna (GPi) deep brain stimulation (DBS) in patients with Parkinson disease (PD).
Methods
Fifty-two subjects with moderate-to-advanced PD were randomized to either unilateral STN or GPi DBS. Right or alternatively left sided stimulation was chosen to address the side of the body with the most bothersome symptoms. The co-primary outcome measures were the change in the 8 subscales of the Visual Analog Mood Scale (VAMS), and the change in the 2 versions of verbal fluency (i.e. semantic and letter), at 7 months post-DBS in the optimal setting compared to the pre-DBS state. In addition, at 7 months post-DBS, after subjects underwent initial evaluation off medications and on optimized DBS therapy, they were tested in four randomized and counterbalanced conditions (optimal DBS, ventral DBS, dorsal DBS, and off DBS) while remaining off medication. Secondary outcome measures then compared the differences in the VAMS items and verbal fluency subscales within the 4 DBS conditions at 7 months, and the change in the VAMS items and verbal fluency subscales from the pre-DBS state to the other 3 DBS conditions (ventral, dorsal and off ) at 7 months.
Results
Forty-five subjects (23 GPi and 22 STN) completed the protocol. The study revealed no significant difference between STN and GPi DBS in the change of co-primary mood and cognitive outcomes from pre- to post-DBS in the optimal setting (Hotelling's T2 test: p=0.16 and 0.08 respectively). When comparing the 4 DBS conditions at 7 months, subjects in both targets were less “happy”, less “energetic” and more “confused” when stimulated ventrally to the optimal stimulation site. When comparing the other 3 DBS conditions (ventral, dorsal and off DBS) to the pre-DBS state, the STN group showed a larger deterioration of letter verbal fluency scores than the GPi group, especially in the off DBS state. A 12-point mean improvement in the UPDRS motor subscale was seen post DBS, but there was no significant difference between targets.
Interpretations
There were no significant differences in in the co-primary outcome measures of mood and cognition between STN and GPi in the optimal DBS state.. However, adverse mood effects were noted when stimulating ventrally to the optimal site in both targets. Furthermore, a worsening for letter verbal fluency was noted in the 3 non-optimal post-DBS states in the STN target only. The persistence of deterioration in verbal fluency in the off DBS state at 7 months is, suggestive of a surgical rather than a stimulation-induced effect at the STN target. STN and GPi DBS resulted in similar motor improvement.
doi:10.1002/ana.21596
PMCID: PMC2692580  PMID: 19288469
GPi; STN; DBS; Mood; Cognition; Side Effects; verbal fluency; motor; UPDRS
10.  Identification of the subthalamic nucleus in deep brain stimulation surgery with a novel wavelet-derived measure of neural background activity 
Journal of neurosurgery  2009;111(4):767-774.
Object
A wavelet-based measure was developed to quantitatively assess neural background activity taken during surgical neurophysiological recordings to localize the boundaries of the subthalamic nucleus during target localization for deep brain stimulator implant surgery.
Methods
Neural electrophysiological data was recorded from 14 patients (20 tracks, n = 275 individual recording sites) with dopamine-sensitive idiopathic Parkinson’s disease during the target localization portion of deep brain stimulator implant surgery. During intraoperative recording the STN was identified based upon audio and visual monitoring of neural firing patterns, kinesthetic tests, and comparisons between neural behavior and known characteristics of the target nucleus. The quantitative wavelet-based measure was applied off-line using MATLAB software to measure the magnitude of the neural background activity, and the results of this analysis were compared to the intraoperative conclusions. Wavelet-derived estimates were compared to power spectral density measures.
Results
The wavelet-derived background levels were significantly higher in regions encompassed by the clinically estimated boundaries of the STN than in surrounding regions (STN: 225 ± 61 μV vs. ventral to STN: 112 ± 32 μV, and dorsal to STN: 136 ± 66 μV). In every track, the absolute maximum magnitude was found within the clinically identified STN. The wavelet-derived background levels provided a more consistent index with less variability than power spectral density.
Conclusions
The wavelet-derived background activity assessor can be calculated quickly, requires no spike sorting, and can be reliably used to identify the STN with very little subjective interpretation required. This method may facilitate rapid intraoperative identification of subthalamic nucleus borders.
doi:10.3171/2008.11.JNS08392
PMCID: PMC4763615  PMID: 19344225
Subthalamic nucleus; deep brain stimulation; Parkinson’s disease; neurosurgery
11.  T2-relaxometry predicts outcome of DBS in idiopathic Parkinson's disease 
NeuroImage : Clinical  2016;12:832-837.
Introduction
Deep brain stimulation (DBS) nowadays is a well-established treatment of motor symptoms in Parkinson's disease. The subthalamic nucleus (STN) is a common target for DBS, because motor improvements have been shown to be superior to best medical therapy, if DBS electrodes have been appropriately positioned. DBS target identification can be assisted by MRI beyond structural imaging by spatially resolved measurement of T2-relaxation times (T2r).
Aim
We pose the question, whether T2r of the STN is linked to the severity of the disease and whether outcome of DBS may be correlated to an asymmetric manifestation of the disease. Further, we investigated if abnormal T2r in the STN may be predictive for outcome of DBS.
Methods
Twelve patients underwent preoperative MR imaging including a multi echo relaxometry sequence (3 Tesla, Siemens Medical Systems, Erlangen, Germany) ahead of DBS. T2r were determined for STN, substantia nigra (SN), red nucleus (RN) and centrum semiovale (CSO). Unified Parkinson's disease Rating Scale (UPDRS) scores were tested before and after DBS. Patients' T2r and deduced values representing left-right asymmetry of measurements were correlated with UPDRS scores and measures for outcome of DBS. Furthermore, patients' T2r were compared with T2r measurements in 12 healthy controls (HC).
Results
Patients' T2r for SN (mean 45.4 ms ± 4.4 ms) and STN (mean 56.4 ms ± 3.8 ms) were significantly shorter than T2r in HCs for SN (mean 60.7 ± 4.6) and STN (mean 66.1 ms ± 4.0 ms). While no mean T2r asymmetry was found in the SN, patients' mean T2r for STN showed a weakened left-right correlation (Pearson correlation coefficient 0.19 versus 0.72 in HC) indicating asymmetric degeneration. T2r asymmetry was not linked to the more severely affected hemisphere.
The respective lower T2r within the left or right target region was significantly correlated to the outcome in terms of UPDRS III improvement in “off” state (Pearson correlation 0.82 corresponding to p ≪ 0.01). Patients with T2r of STN lower than 50 ms showed no response to DBS in the UPDRS.
The maximum T2r for SN correlated to the improvement between UPDRS “off” minus and “on” (Dopamine response) but failed to predict DBS outcome.
Conclusions
The lower boundaries of T2r in the STN predict motor outcome in DBS. T2r asymmetry in the STN is not associated with increased clinical symptoms, but with response to therapy. Thus, patients with very low T2r may be inappropriate candidates for DBS.
Highlights
•Parkinson's disease features are reflected in spatially resolved measurement of MR T2-relaxation times.•Deep brain stimulation therapy target identification can be assisted by measurement of MR T2-relaxation times.•T2r asymmetry in the subthalamic nucleus is not associated with increased clinical symptoms, but with response to therapy.•Lower boundaries of T2r in the STN predict motor outcome in Deep brain stimulation therapy•Patient selection criteria may be improved by including parameters based on MR relaxometry.
doi:10.1016/j.nicl.2016.09.019
PMCID: PMC5097958  PMID: 27843765
Parkinson's disease; Deep brain stimulation; Subthalamic nucleus; Basal ganglia; T2 relaxometry
12.  THE EFFECTS OF SUBTHALAMIC AND PALLIDAL DEEP BRAIN STIMULATION ON POSTURAL RESPONSES IN PATIENTS WITH PARKINSON'S DISEASE 
Journal of neurosurgery  2012;116(6):1347-1356.
Object
The effect of Deep Brain Stimulation (DBS) for Parkinson's disease (PD) on balance is unclear. The goal of this study was to investigate how automatic postural responses were affected in subjects randomized to either the Subthalamic Nucleus (STN) or the Globus Pallidus interna (GPi) surgery.
Methods
We tested 24 PD subjects who underwent bilateral DBS, 9 PD control subjects without DBS, and 17 age-matched control subjects. Electrode placement site was randomized and blinded to PD subjects and experimenters. Kinematic, kinetic and electromyographic recordings of postural responses to backward disequilibrium via forward translations of the standing surface were recorded in the week prior to surgery while off (OFF) and on antiparkinsonian medication (ON) and then 6 months after surgery in four conditions: off medication with DBS switched off (OFF/OFF), off medication with DBS on (DBS), on medication with DBS off (DOPA), and both medication and DBS on (DBS+DOPA). Stability of the automatic postural response (APR stability) was measured as the difference between the displacement of the center of pressure and the projected location of the center of body mass.
Results
PD subjects had worse APR stability than control subjects. Turning the DBS on at either site improved APR stability compared to the postoperative off condition by lengthening the tibialis response, whereas medication did not show an appreciable effect. The STN group had worse APR stability in their best functional state (DBS+DOPA) six months after the DBS procedure compared to their best functional state (ON levodopa) before the DBS procedure. In contrast, the GPi group and the PD control group showed no change over 6 months. APR stability impairment in the STN group was associated with smaller tibialis response amplitudes, but no change in response latency or co-activation with gastrocnemius.
Conclusions
Turning the DBS current on improved APR stability for both STN and GPi sites. However, there was a detrimental DBS procedural effect for the STN group and this effect was greater than the benefit of the stimulating current, making overall APR stability functionally worse after surgery for the STN group.
doi:10.3171/2012.2.JNS11847
PMCID: PMC3465575  PMID: 22424564
Parkinson's Disease; DBS; Postural control
13.  Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behaviour in Parkinson's disease 
Background: Long term effects of subthalamic nucleus (STN) stimulation on cognition, mood, and behaviour are unknown.
Objective: This study evaluated the cognitive, mood, and behavioural effects of bilateral subthalamic nucleus deep brain stimulation (STN DBS) in patients with Parkinson's disease (PD) followed up for three years.
Methods: A consecutive series of 77 PD patients was assessed before, one, and three years after surgery. Mean (SD) age at surgery was 55 (8). Seven patients died or were lost for follow up. Neuropsychological assessment included a global cognitive scale, memory, and frontal tests. Depression was evaluated using the Beck depression inventory. Assessment of thought disorders and apathy was based on the unified Parkinson's disease rating scale. Reports of the behavioural changes are mainly based on interviews done by the same neuropsychologist at each follow up.
Results: Only two cognitive variables worsened (category fluency, total score of fluency). Age was a predictor of decline in executive functions. Depression improved whereas apathy and thought disorders worsened. Major behavioural changes were two transient aggressive impulsive episodes, one suicide, four suicide attempts, one permanent apathy, one transient severe depression, four psychoses (one permanent), and five hypomania (one permanent).
Conclusions: Comparing baseline, one year, and three year postoperative assessments, STN stimulation did not lead to global cognitive deterioration. Apathy scores mildly increased. Depression scores mildly improved. Behavioural changes were comparatively rare and mostly transient. Single case reports show the major synergistic effects of both medication and stimulation on mood and behaviour, illustrating the importance of a correct postoperative management.
doi:10.1136/jnnp.2002.009803
PMCID: PMC1739075  PMID: 15145995
14.  Subthalamic Nucleus Deep Brain Stimulation Modulate Catecholamine Levels with Significant Relations to Clinical Outcome after Surgery in Patients with Parkinson’s Disease 
PLoS ONE  2015;10(9):e0138462.
Aims
Although subthalamic nucleus deep brain stimulation (STN-DBS) is effective in patients with advanced Parkinson’s disease (PD), its physiological mechanisms remain unclear. Because STN-DBS is effective in patients with PD whose motor symptoms are dramatically alleviated by L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, the higher preoperative catecholamine levels might be related to the better clinical outcome after surgery. We aimed to examine the correlation between the preoperative catecholamine levels and postoperative clinical outcome after subthalamic nucleus deep brain stimulation. The effectiveness of STN-DBS in the patient who responded well to dopaminergic medication suggest the causal link between the dopaminergic system and STN-DBS. We also examined how catecholamine levels were modulated after subthalamic stimulation.
Methods
In total 25 patients with PD were enrolled (Mean age 66.2 ± 6.7 years, mean disease duration 11.6 ± 3.7 years). Mean levodopa equivalent doses were 1032 ± 34.6 mg before surgery. Cerebrospinal fluid and plasma catecholamine levels were measured an hour after oral administration of antiparkinsonian drugs before surgery. The mean Unified Parkinson’s Disease Rating Scale scores (UPDRS) and the Parkinson’s disease Questionnaire-39 (PDQ-39) were obtained before and after surgery. Of the 25 patients, postoperative cerebrospinal fluid and plasma were collected an hour after oral administration of antiparkinsonian drugs during on stimulation at follow up in 11 patients.
Results
Mean levodopa equivalent doses significantly decreased after surgery with improvement in motor functions and quality of life. The preoperative catecholamine levels had basically negative correlations with postoperative motor scores and quality of life, suggesting that higher preoperative catecholamine levels were related to better outcome after STN-DBS. The preoperative plasma levels of L-DOPA had significantly negative correlations with postoperative UPDRS- III score in off phase three months after STN-DBS. The preoperative cerebrospinal fluid (CSF) 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxytryptamine (5-HT) levels had significantly negative correlations with postoperative UPDRS- III score in off phase one year after STN-DBS and the preoperative CSF homovanilic acid (HVA) levels had significant negative correlations with postoperative UPDRS- III score in on phase three months after STN-DBS. In PDQ-39 SI (summary index), preoperative plasma dopamine (DA) level had significantly negative correlations with postoperative PDQ-39 SI one year after STN-DBS suggesting that higher preoperative plasma DA level resulted in better quality of life (QOL) one year after STN-DBS. The stepwise multiple linear regression study revealed that higher preoperative plasma HVA levels had negative influence on the postoperative motor symptoms (i.e., increase in the score of UPDRS), whereas higher preoperative CSF L-DOPA levels had positive influence on the postoperative motor symptoms and QOL (decrease in the score of UPDRS and PDQ-39 SI) The catecholamine levels were not significantly reduced postoperatively in 11 patients despite the significant reduction in levodopa equivalent doses. Unexpectedly, CSF HVA levels significantly increased from 0.00089±0.0003 ng/μl to 0.002±0.0008 ng/μl after STN-DBS.
Conclusion
The preoperative catecholamine levels might affect the postoperative motor symptoms and quality of life. The catecholamine levels were not significantly reduced postoperatively despite the significant reduction in levodopa equivalent doses.
doi:10.1371/journal.pone.0138462
PMCID: PMC4578924  PMID: 26394059
15.  Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study 
Brain : a journal of neurology  2009;132(Pt 5):1376-1385.
Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson’s disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson’s disease patients with impulse control disorders. We describe results of a [11C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson’s disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson’s disease patients may provide a model into the pathophysiology of this disorder.
doi:10.1093/brain/awp054
PMCID: PMC3479148  PMID: 19346328 CAMSID: cams2369
Parkinson’s disease; dopamine; impulse control disorders; pathological gambling; PET; functional imaging
16.  Impact of Bilateral Subthalamic Stimulation on Motor/Cognitive Functions in Parkinson's Disease 
Neurologia Medico-Chirurgica  2014;54(7):529-536.
It is still unclear whether deep brain stimulation targeted to the bilateral subthalamic nucleus (STN-DBS) affects cognitive function in Parkinson's disease (PD). This prospective study was aimed to systemically evaluate the impact of bilateral STN-DBS on motor and cognitive functions in patients with PD. This study included totally 11 Japanese patients with medically intolerant PD. Neurological and cognitive status was precisely evaluated before and 1 year after bilateral STN-DBS, using unified Parkinson's disease rating scale (UPDRS), levodopa equivalent doses, mini-mental state examination (MMSE), Japanese adult reading test (JART), repeatable battery for the assessment of neuropsychological status (RBANS), and Wechsler adult intelligence scale-revised (WAIS-R). Preoperative RBANS and WAIS-R identified cognitive dysfunction that could not be detected by MMSE and JART. Before surgery, PD patients had significantly impaired immediate memory and attention. Motor function significantly improved 1 year after bilateral STN-DBS. Bilateral STN-DBS did not affect any score on cognitive examinations. However, postoperative improvements of total score on RBANS and performance intelligence quotient (PIQ) scores on WAIS-R were closely related to those of UPDRS part III off (R2 = 0.61, P < 0.01; R2 = 0.39, P < 0.05, respectively). These findings strongly suggest that bilateral STN-DBS may significantly improve cognitive function in a certain subgroup of patients whose therapeutic effects on motor function are prominent.
doi:10.2176/nmc.oa.2013-0364
PMCID: PMC4533462  PMID: 24872253
deep brain stimulation; Parkinson's disease; subthalamic nucleus; cognitive function
17.  Subthalamic deep brain stimulation improves smooth pursuit and saccade performance in patients with Parkinson’s disease 
Background
Deep brain stimulation (DBS) in the subthalamic nucleus (STN) significantly reduces symptoms of Parkinson’s disease (PD) such as bradykinesia, tremor and rigidity. It also reduces the need for anti-PD medication, and thereby potential side-effects of L-Dopa. Although DBS in the STN is a highly effective therapeutic intervention in PD, its mechanism and effects on oculomotor eye movement control and particularly smooth pursuit eye movements have to date rarely been investigated. Furthermore, previous reports provide conflicting information. The aim was to investigate how DBS in STN affected oculomotor performance in persons with PD using novel analysis techniques.
Methods
Twenty-five patients were eligible (22 males, 3 females) according to the clinical inclusion criteria: idiopathic PD responsive to L-Dopa and having had bilateral STN stimulation for at least one year to ensure stable DBS treatment. Fifteen patients were excluded due to the strict inclusion criteria applied to avoid interacting and confounding factors when determining the effects of DBS applied alone without PD medication. One patient declined participation. Nine PD patients (median age 63, range 59–69 years) were assessed after having their PD medications withdrawn overnight. They were examined with DBS ON and OFF, with the ON/OFF order individually randomized.
Results
DBS ON increased smooth pursuit velocity accuracy (p < 0.001) and smooth pursuit gain (p = 0.005), especially for faster smooth pursuits (p = 0.034). DBS ON generally increased saccade amplitude accuracy (p = 0.007) and tended to increase peak saccade velocity also (p = 0.087), specifically both saccade velocity and amplitude accuracy for the 20 and 40 degree saccades (p < 0.05). Smooth pursuit latency tended to be longer (p = 0.090) approaching normal with DBS ON. Saccade latency was unaffected.
Conclusions
STN stimulation from DBS alone significantly improved both smooth pursuit and saccade performance in patients with PD. The STN stimulation enhancement found for oculomotor performance suggests clear positive implications for patients’ ability to perform tasks that rely on visual motor control and visual feedback. The new oculomotor analysis methods provide a sensitive vehicle to detect subtle pathological modifications from PD and the functional enhancements produced by STN stimulation from DBS alone.
doi:10.1186/1743-0003-10-33
PMCID: PMC3621588  PMID: 23551890
Parkinson’s disease; Deep brain stimulation; Subthalamic nucleus; Oculomotor functions
18.  Cerebral blood flow responses to dorsal and ventral STN DBS correlate with gait and balance responses in Parkinson disease 
Experimental neurology  2012;241:105-112.
Objectives
The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on gait and balance vary and the underlying mechanisms remain unclear. DBS location may alter motor benefit due to anatomical heterogeneity in STN. The purposes of this study were to (1) compare effects of DBS of dorsal (D-STN) versus ventral (V-STN) regions on gait, balance and regional cerebral blood flow (rCBF) and (2) examine relationships between changes in rCBF and changes in gait and balance induced by D-STN or V-STN DBS.
Methods
We used a validated atlas registration to locate and stimulate through electrode contacts in D-STN and V-STN regions of 37 people with Parkinson disease. In a within-subjects, double-blind and counterbalanced design controlled for DBS settings, we measured PET rCBF responses in a priori regions of interest and quantified gait and balance during DBS Off, unilateral D-STN DBS and unilateral V-STN DBS.
Results
DBS of either site increased stride length without producing significant group-level changes in gait velocity, cadence or balance. Both sites increased rCBF in subcortical regions and produced variable changes in cortical and cerebellar regions. DBS-induced changes in gait velocity related to premotor cortex rCBF changes during V-STN DBS (r = −0.40, p = 0.03) and to rCBF changes in the cerebellum anterior lobe during D-STN DBS (r = −0.43, p = 0.02).
Conclusions
DBS-induced changes in gait corresponded to rCBF responses in selected cortical and cerebellar regions. These relationships differed during D-STN versus V-STN DBS, suggesting DBS acts through distinct neuronal pathways dependent on DBS location.
doi:10.1016/j.expneurol.2012.12.003
PMCID: PMC3570746  PMID: 23262122
deep brain stimulation; gait; positron emission tomography; Parkinson disease; subthalamic nucleus
19.  Stimulation of the subthalamic nucleus in Parkinson's disease: a 5 year follow up 
Background: The short term benefits of bilateral stimulation of the subthalamic nucleus (STN) in patients with advanced levodopa responsive Parkinson's disease (PD) are well documented, but long term benefits are still uncertain.
Objectives: This study provides a 5 year follow up of PD patients treated with stimulation of the STN.
Methods: Thirty seven consecutive patients with PD treated with bilateral STN stimulation were assessed prospectively 6, 24, and 60 months after neurosurgery. Parkinsonian motor disability was evaluated with and without levodopa treatment, with and without bilateral STN stimulation. Neuropsychological and mood assessments included the Mattis Dementia Rating Scale, the frontal score, and the Montgomery-Asberg Depression Rating Scale (MADRS).
Results: No severe peri- or immediate postoperative side effects were observed. Six patients died and one was lost to follow up. Five years after neurosurgery: (i) activity of daily living (Unified Parkinson Disease Rating Scale (UPDRS) II) was improved by stimulation of the STN by 40% ("off" drug) and 60% ("on" drug); (ii) parkinsonian motor disability (UPDRS III) was improved by 54% ("off" drug) and 73% ("on" drug); (iii) the severity of levodopa related motor complications was decreased by 67% and the levodopa daily doses were reduced by 58%. The MADRS was unchanged, but cognitive performance declined significantly. Persisting adverse effects included eyelid opening apraxia, weight gain, addiction to levodopa treatment, hypomania and disinhibition, depression, dysarthria, dyskinesias, and apathy.
Conclusions: Despite moderate motor and cognitive decline, probably due to disease progression, the marked improvement in motor function observed postoperatively was sustained 5 years after neurosurgery.
doi:10.1136/jnnp.2005.063206
PMCID: PMC1739461  PMID: 16291886
20.  Parkinson's disease 
BMJ Clinical Evidence  2007;2007:1203.
Introduction
Around 1% of adults have Parkinson’s disease, with a median time of 9 years between diagnosis and death.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments in people with early-stage Parkinson’s disease? What are the effects of adding other treatments in people with Parkinson’s disease who have motor complications from levodopa? What are the effects of surgery in people with later Parkinson’s disease? What are the effects of nursing and rehabilitation treatments in people with Parkinson’s disease? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 59 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding a catechol-methyl transferase inhibitor, or dopamine agonist to levodopa; amantadine; dopamine agonists; levodopa (immediate-release, modified-release); monoamine oxidase B inhibitors; occupational therapy; pallidal deep brain stimulation; pallidotomy; Parkinson’s disease nurse specialist interventions; physiotherapy; speech and language therapy; subthalamic nucleus deep brain stimulation; subthalamotomy; swallowing therapy; thalamic deep brain stimulation; and thalamotomy.
Key Points
Around 1% of adults have Parkinson's disease, with a median time of 9 years between diagnosis and death.
Levodopa is considered effective at reducing symptoms in early Parkinson's disease, but can cause irreversible dyskinesias and motor fluctuation in the long term. We don't know whether levodopa, or any other treatment, improves survival. Modified-release levodopa seems no more effective than immediate-release levodopa at improving symptoms, and delaying motor complications.
Monoamine oxidase B inhibitors (MAOBIs) may improve symptoms, reduce motor fluctuations, and delay the need for levodopa, but can cause adverse effects.
We don't know whether amantadine is beneficial for people with early Parkinson's disease, although it is currently used to treat dyskinesia. People taking amantadine for dyskinesia in early Parkinson's may have a higher risk of psychiatric adverse effects in the later stages of the disease.
Adding a catechol-O-methyl transferase (COMT) inhibitor or dopamine agonist to levodopa, or using dopamine agonists as monotherapy, may reduce ‘off' time and improve symptoms compared with levodopa alone, but can cause adverse effects. The COMT inhibitor tolcapone can cause fatal hepatic toxicity.
Surgery may be considered in people with later Parkinson's disease, but can cause fatalities. Post-operative complications include speech problems and apraxia. Although evidence is lacking, many clinicians feel that both pallidal deep brain stimulation and subthalamic nucleus deep brain stimulation improve symptoms of advanced Parkinson's disease.Bilateral subthalamic nucleus deep brain stimulation may lead to greater improvement in motor symptoms, but more cognitive impairment, than pallidal deep brain stimulation. Pallidal deep brain stimulation is associated with severe intraoperative complications.Adding subthalamic nucleus deep brain stimulation to medical treatment may improve quality of life and motor symptoms compared with medical treatment alone or other forms of surgery. It can, however, cause neurological complications, neuropsychological adverse effects, and fatal surgical complications.Unilateral pallidotomy may improve symptoms and function more than medical treatment, but may be less effective than bilateral subthalamic stimulation.We don't know whether subthalamotomy or thalamotomy are effective.
Nurse specialist interventions, occupational therapy, physiotherapy, speech and language therapy and swallowing therapy are generally considered effective and safe in people with Parkinson's disease, although few studies have been found.
PMCID: PMC2943804  PMID: 19454106
21.  Subthalamic Nucleus Deep Brain Stimulation Does Not Improve Visuo-Motor Impairment in Parkinson’s Disease 
PLoS ONE  2013;8(6):e65270.
Objective
To evaluate how bilateral subthalamic nucleus deep brain stimulation (STN-DBS) affects visuo-motor coordination (VMC) in patients with Parkinson’s disease (PD).
Background
VMC involves multi-sensory integration, motor planning, executive function and attention. VMC deficits are well-described in PD. STN-DBS conveys marked motor benefit in PD, but pyscho-cognitive complications are recognized and the effect on VMC is not known.
Methods
Thirteen PD patients with bilateral STN-DBS underwent neurological, cognitive, and mood assessment before VMC testing with optimal DBS stimulation parameters (‘on-stimulation’) and then, on the same day without any medication changes, after DBS silencing and establishing motor function deterioration (‘off-stimulation’). Twelve age-matched healthy controls performed 2 successive VMC testing sessions, with a break of similar duration to that of the PD group. The computer cursor was controlled with a dome-shaped ‘mouse’ hidden from view that minimized tremor effects. Movement duration, hand velocity, tracking continuity, directional control variables, and feedback utilization variables were measured. MANOVA was performed on (1) clinically measured motor function, (2) VMC performance and (3) mood and attention, looking for main and interaction effects of: (1) group (controls/PD), (2) test-order (controls: first/second, PD: on-stimulation/off-stimulation), (3) path (sine/square/circle) and (4) hand (dominant/non-dominant).
Results
Unified PD Rating Scale (UPDRS) Part III worsened off-stimulation versus on-stimulation (mean: 42.3 versus 21.6, p = 0.02), as did finger tapping (p = 0.02), posture-gait (p = 0.01), upper limb function (p<0.001) and backwards digit span (p = 0.02). Stimulation state did not affect mood. PD patients performed worse in non-velocity related VMC variables than controls (F(5,18) = 8.5, p<0.001). In the control group there were significant main effects of hand (dominant/non-dominant), path (sine/square/circle) and test-order (Test_1/Test_2). In the PD group, hand and path effects, but no test-order (on-stimulation/off-stimulation), were found.
Conclusions
‘Low-level’ clinically-measured motor function responds to STN-DBS but ‘high-level’ motor and cognitive functions relating to VMC may be unresponsive to STN-DBS.
doi:10.1371/journal.pone.0065270
PMCID: PMC3679151  PMID: 23776460
22.  Does bilateral stimulation of the subthalamic nucleus aggravate apathy in Parkinson's disease? 
Objective: High frequency stimulation of the subthalamic nucleus (STN) dramatically decreases motor disability in patients with Parkinson"s disease (PD), but has been reported to aggravate apathy. The aim of this study was to analyse the effect of STN stimulation on motivation and reward sensitivity in a consecutive series of PD patients.
Methods: Apathy and reward sensitivity (Apathy Scale, Stimulus-Reward Learning, Reversal, Extinction, and Gambling tasks) were assessed in 18 PD patients treated by bilateral STN stimulation ("on" and "off" conditions) compared with 23 matched patients undergoing long term treatment with levodopa ("on" and "off" conditions).
Results: Apathy decreased under both STN stimulation and levodopa treatment, whereas explicit and implicit stimulus reward learning was unchanged.
Conclusions: Bilateral STN stimulation in PD patients does not necessarily have a negative effect on motivation and reward sensitivity and can even improve apathy provided patients have been appropriately selected for neurosurgery.
doi:10.1136/jnnp.2003.033258
PMCID: PMC1739659  PMID: 15897497
23.  Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: evaluation of active electrode contacts 
Background: The subthalamic nucleus is the preferred target for deep brain stimulation in patients with advanced Parkinson's disease. The site of permanent stimulation is the subject of ongoing debate, as stimulation both within and adjacent to the subthalamic nucleus may be effective.
Objective: To assess the position of active electrode contacts in relation to the dorsal margin of the subthalamic nucleus as determined by intraoperative microrecordings and magnetic resonance imaging (MRI).
Methods: In 25 patients suffering from severe levodopa sensitive parkinsonism, deep brain stimulating electrodes (n = 49) were implanted following mapping of the subthalamic nucleus by microrecording and microstimulation along five parallel tracks. Postoperative stereotactic radiography and fusion of pre- and postoperative MRI studies were used to determine the stereotactic position relative to the midcommissural point of the most effective electrode contacts selected for permanent stimulation (n = 49). Intraoperative microrecordings were analysed retrospectively to define the dorsal margin of the subthalamic nucleus. In cases where the dorsal margin could be defined in at least three microrecording tracks (n = 37) it was correlated with the position of the active contact using an algorithm developed for direct three dimensional comparisons.
Results: Stimulation of the subthalamic nucleus resulted in marked improvement in levodopa sensitive parkinsonian symptoms and levodopa induced dyskinesias, with significant improvement in UPDRS III scores. In several instances, projection of the electrode artefacts onto the T2 weighted MRI visualised subthalamic nucleus of individual patients suggested that the electrodes had passed through the subthalamic nucleus. When the actual position of active electrode contacts (n = 35) was correlated with the dorsal margin of the subthalamic nucleus as defined neurophysiologically, most contacts were located either in proximity (± 1.0 mm) to the dorsal border of the subthalamic nucleus (32.4%) or further dorsal within the subthalamic region (37.8%). The other active contacts (29.7%) were detected within the dorsal (sensorimotor) subthalamic nucleus. The average position of all active contacts (n = 49) was 12.8 mm (± 1.0) lateral, 1.9 mm (± 1.4) posterior, and 1.6 mm (± 2.1) ventral to the midcommissural point.
Conclusions: Subthalamic nucleus stimulation appears to be most effective in the border area between the upper subthalamic nucleus (sensorimotor part) and the subthalamic area containing the zona incerta, fields of Forel, and subthalamic nucleus projections.
doi:10.1136/jnnp.74.8.1036
PMCID: PMC1738607  PMID: 12876231
24.  Reduced Vglut2/Slc17a6 Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption 
eNeuro  2016;3(5):ENEURO.0264-16.2016.
Visual Abstract
The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson’s disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the vesicular glutamate transporter 2 gene (Vglut2/Slc17a6) and that reduction of Vglut2 mRNA levels within the STN of mice [conditional knockout (cKO)] causes reduced postsynaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior, whereas biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified, which likely accounts for the observed alterations. Rare genetic variants of the human VGLUT2 gene exist, and this study shows that reduced Vglut2/Slc17a6 gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and the mesostriatal dopamine system.
doi:10.1523/ENEURO.0264-16.2016
PMCID: PMC5041164  PMID: 27699212
dopamine; dynorphin; glutamate; rearing; reward; self-administration
25.  Tuning the Brake While Raising the Stake: Network Dynamics during Sequential Decision-Making 
The Journal of Neuroscience  2016;36(19):5417-5426.
When gathering valued goods, risk and reward are often coupled and escalate over time, for instance, during foraging, trading, or gambling. This escalating frame requires agents to continuously balance expectations of reward against those of risk. To address how the human brain dynamically computes these tradeoffs, we performed whole-brain fMRI while healthy young individuals engaged in a sequential gambling task. Participants were repeatedly confronted with the option to continue with throwing a die to accumulate monetary reward under escalating risk, or the alternative option to stop to bank the current balance. Within each gambling round, the accumulation of gains gradually increased reaction times for “continue” choices, indicating growing uncertainty in the decision to continue. Neural activity evoked by “continue” choices was associated with growing activity and connectivity of a cortico-subcortical “braking” network that positively scaled with the accumulated gains, including pre-supplementary motor area (pre-SMA), inferior frontal gyrus, caudate, and subthalamic nucleus (STN). The influence of the STN on continue-evoked activity in the pre-SMA was predicted by interindividual differences in risk-aversion attitudes expressed during the gambling task. Furthermore, activity in dorsal anterior cingulate cortex (ACC) reflected individual choice tendencies by showing increased activation when subjects made nondefault “continue” choices despite an increasing tendency to stop, but ACC activity did not change in proportion with subjective choice uncertainty. Together, the results implicate a key role of dorsal ACC, pre-SMA, inferior frontal gyrus, and STN in computing the trade-off between escalating reward and risk in sequential decision-making.
SIGNIFICANCE STATEMENT Using a paradigm where subjects experienced increasing potential rewards coupled with increasing risk, this study addressed two unresolved questions in the field of decision-making: First, we investigated an “inhibitory” network of regions that has so far been investigated with externally cued action inhibition. In this study, we show that the dynamics in this network under increasingly risky decisions are predictive of subjects' risk attitudes. Second, we contribute to a currently ongoing debate about the anterior cingulate cortex's role in sequential foraging decisions by showing that its activity is related to making nondefault choices rather than to choice uncertainty.
doi:10.1523/JNEUROSCI.3191-15.2016
PMCID: PMC4863066  PMID: 27170137
ACC; action selection; conflict; inhibition; pre-SMA

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