Subthalamic nucleus deep brain stimulation connectivity related to apathy outcomes in Parkinson's disease.

Preclinical studies show a link between subthalamic nucleus (STN) deep brain stimulation (DBS) and neuroprotection of nigrostriatal dopamine (DA) neurons, potentially through brain-derived neurotrophic factor (BDNF) signaling. However, the question of whether DBS of the STN can be disease-modifying in Parkinson's disease (PD) remains unanswered. In particular, the impact of STN DBS on α-synuclein (α-syn) aggregation, inclusion-associated neuroinflammation, and BDNF levels has yet to be examined in the context of synucleinopathy. To address this, we examined the effects of STN DBS on BDNF using the α-syn preformed fibril (PFF) model in male rats. While PFF injection resulted in accumulation of phosphorylated α-syn (pSyn) inclusions in the substantia nigra pars compacta (SNpc) and cortical areas, STN DBS did not impact PFF-induced accumulation of pSyn inclusions in the SNpc. In addition, nigral pSyn inclusions were associated with increased microgliosis and astrogliosis; however, the magnitude of these processes was not altered by STN DBS. Total BDNF protein was not impacted by pSyn inclusions, but the normally positive association of nigrostriatal and corticostriatal BDNF was reversed in rats with PFF-induced nigrostriatal and corticostriatal inclusions. Despite this, rats receiving both STN DBS and PFF injection showed increased BDNF protein in the striatum, which partially restored the normal corticostriatal relationship. Our results suggest that pathologic α-syn inclusions disrupt anterograde BDNF transport within nigrostriatal and corticostriatal circuitry. Further, STN DBS has the potential to exert protective effects by modifying the long-term neurodegenerative consequences of synucleinopathy.SIGNIFICANCE STATEMENT An increase in brain-derived neurotrophic factor (BDNF) has been linked to the neuroprotection elicited by subthalamic nucleus (STN) deep brain stimulation (DBS) in neurotoxicant models of Parkinson's disease (PD). However, whether STN DBS can similarly increase BDNF in nigrostriatal and corticostriatal circuitry in the presence of α-synuclein (α-syn) inclusions has not been examined. We examined the impact of STN DBS on rats in which accumulation of α-syn inclusions is induced by injection of α-syn preformed fibrils (PFFs). STN DBS significantly increased striatal BDNF protein in rats seeded with α-syn inclusions and partially restored the normal corticostriatal BDNF relationship. These findings suggest that STN DBS can drive BDNF in the parkinsonian brain and retains the potential for neuroprotection in PD.

ObjectiveTo compare the therapeutic and adverse effects of globus pallidus interna (GPi) and subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of advanced Parkinson’s disease (PD).MethodsWe retrospectively analyzed the clinical data of patients with PD who underwent GPi (n = 14) or STN (n = 28) DBS surgery between April 2002 and May 2014. The subjects were matched for age at surgery and disease duration. The Unified Parkinson’s Disease Rating Scale (UPDRS) scores and levodopa equivalent dose (LED) at baseline and 12 months after surgery were used to assess the therapeutic effects of DBS. Adverse effects were also compared between the two groups.ResultsAt 12 months, the mean changes in the UPDRS total and part I–IV scores did not differ significantly between the two groups. However, the subscores for gait disturbance/postural instability and dyskinesia were significantly more improved after GPi DBS than those after STN DBS (p = 0.024 and 0.016, respectively). The LED was significantly more reduced in patients after STN DBS than that after GPi DBS (p = 0.004). Serious adverse effects did not differ between the two groups (p = 0.697).ConclusionThe patients with PD showed greater improvement in gait disturbance/postural instability and dyskinesia after GPi DBS compared with those after STN DBS, although the patients had a greater reduction in LED after STN DBS. These results may provide useful information for optimal target selection for DBS in PD.

Objective:To investigate hemispheric effects of directional versus ring subthalamic nucleus (STN) deep brain stimulation (DBS) surgery on cognitive function in patients with advanced Parkinson’s disease (PD).Methods:We examined 31 PD patients (Left STN n = 17; Right STN n = 14) who underwent unilateral subthalamic nucleus (STN) DBS as part of a NIH-sponsored randomized, cross-over, double-blind (ring vs directional) clinical trial. Outcome measures were tests of verbal fluency, auditory-verbal memory, and response inhibition. First, all participants were pooled together to study the effects of directional versus ring stimulation. Then, we stratified the groups by surgery hemisphere and studied the longitudinal changes in cognition post-unilateral STN DBS.Results:Relative to pre-DBS cognitive baseline performances, there were no group changes in cognition following unilateral DBS for either directional or ring stimulation. However, assessment of unilateral DBS by hemisphere revealed a different pattern. The left STN DBS group had lower verbal fluency than the right STN group (t(20.66 = −2.50, p = 0.02). Over a period of eight months post-DBS, verbal fluency declined in the left STN DBS group (p = 0.013) and improved in the right STN DBS group over time (p < .001). Similarly, response inhibition improved following right STN DBS (p = 0.031). Immediate recall did not significantly differ over time, nor was it affected by implant hemisphere, but delayed recall equivalently declined over time for both left and right STN DBS groups (left STN DBS p = 0.001, right STN DBS differ from left STN DBS p = 0.794).Conclusions:Directional and ring DBS did not differentially or adversely affect cognition over time. Regarding hemisphere effects, verbal fluency decline was observed in those who received left STN DBS, along with the left and right STN DBS declines in delayed memory. The left STN DBS verbal fluency decrement is consistent with prior bilateral DBS research, likely reflecting disruption of the basal-ganglia-thalamocortical network connecting STN and inferior frontal gyrus. Interestingly, we found an improvement in verbal fluency and response inhibition following right STN DBS. It is possible that unilateral STN DBS, particularly in the right hemisphere, may mitigate cognitive decline.

This study examined the long-term effects of chronic subthalamic nucleus (STN) deep brain stimulation (DBS) using both clinical evaluation and laboratory motor control measures. Over a 5-year time period, changes in the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) and movement speed and strength at the ankle joint were evaluated on and off STN DBS in eight patients with Parkinson's disease (PD). Four patients were also studied at the elbow joint. Patients with PD originally received unilateral STN DBS between years 2001 and 2003. They were re-evaluated after 5 years of long-term STN DBS between years 2006-2008. At baseline (year 0) and after 5 years, patients with PD were tested off treatment and on STN DBS. In each testing condition, patients performed ballistic, single degree of freedom ankle dorsiflexion and ankle plantarflexion movements and peak velocity was calculated. Patients also performed maximal voluntary contractions at the ankle joint in both directions, and peak torque was calculated. Results showed increased motor UPDRS scores from year 0 to year 5, but STN DBS was efficacious in reducing them. In contrast to the increase in motor UPDRS scores, motor control results showed a marked improvement in peak velocity and peak torque over the 5-year time period in the off treatment condition, and STN DBS was efficacious by improving both peak velocity and peak torque. The current findings suggest that 5 years of chronic STN DBS can have beneficial effects on the motor system over the long term in discrete motor tasks in which maximal effort and maximal neural output is required.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) is an effective treatment for parkinsonian motor signs. Though its therapeutic mechanisms remain unclear, it has been suggested that antidromic activation of the primary motor cortex (M1) plays a significant role in mediating its therapeutic effects. This study tested the hypothesis that antidromic activation of M1 is a prominent feature underlying the therapeutic effect of STN and GPi DBS. Single-unit activity in M1 was recorded using high-density microelectrode arrays in two parkinsonian nonhuman primates each implanted with DBS leads targeting the STN and GPi. Stimulation in each DBS target had similar therapeutic effects, however, antidromic activation of M1 was only observed during STN DBS. Although both animals undergoing STN DBS had similar beneficial effects, the proportion of antidromic-classified cells in each differed, 30 versus 6%. Over 4 h of continuous STN DBS, antidromic activation became less robust, whereas therapeutic benefits were maintained. Although antidromic activation waned over time, synchronization of spontaneous spiking in M1 was significantly reduced throughout the 4 h. Although we cannot discount the potential therapeutic role of antidromic M1 activation at least in the acute phase of STN DBS, the difference in observed antidromic activation between animals, and target sites, raise questions about its hypothesized role as the primary mechanism underlying the therapeutic effect of DBS. These results lend further support that reductions in synchronization at the level of M1 are an important factor in the therapeutic effects of DBS.SIGNIFICANCE STATEMENT Recently there has been great interest and debate regarding the potential role of motor cortical activation in the therapeutic mechanisms of deep brain stimulation (DBS) for Parkinson's disease. In this study we used chronically implanted high density microelectrode arrays in primary motor cortex (M1) to record neuronal population responses in parkinsonian nonhuman primates during subthalamic nucleus (STN) DBS and globus pallidus internus (GPi) DBS. Our results suggest a contribution of antidromic activation of M1 during STN DBS in disrupting synchronization in cortical neuronal populations; however, diminishing antidromic activity over time, and differences in observed antidromic activation between animals and target sites with antidromic activation not observed during GPi DBS, raise questions about its role as the primary mechanism underlying the therapeutic effect of DBS.

Subthalamic nucleus (STN) and globus pallidus internus (GPI) deep brain stimulation (DBS) effectively treat motor symptoms in Parkinson's disease (PD) but may be associated with cognitive and psychiatric changes in some patients. Evaluation of changes in cognitive and psychiatric symptoms following DBS is complicated by changes in these symptoms that occur as part of the natural disease course. The aim of this study was to evaluate whether electrode position was associated with changes in neurocognitive symptoms in patients who underwent STN and GPI DBS. A single-institution retrospective cohort study was conducted on patients with PD who underwent DBS from 2008 to 2019. Cognitive and psychiatric outcomes included Beck Depression Inventory II (BDI-II) score, presence of impulsive-compulsive behavior (ICB), Mini-Mental State Examination (MMSE) score, and overall cognitive status grade determined by comprehensive neuropsychology testing (normal, mild impairment, moderate impairment, and dementia). Pre- and postoperative comparisons were performed using a Wilcoxon signed-rank test or paired t-test. Patients with and without cognitive decline were compared using a Mann-Whitney U-test or unpaired t-test. A chi-square test was used for categorical comparisons. One hundred thirty patients were included (mean age 62.5 ± 7.9 years). At a mean postoperative follow-up from DBS of 13.0 ± 12.7 (range 6-66) months, there was an improvement in ICB (26.3% preoperatively vs 15.0% postoperatively, p = 0.017), but a decline in MMSE score (28.6 ± 1.6 vs 27.6 ± 2.0, p < 0.001) and overall cognitive status (normal: 66.2% vs 39.2%; mild: 12.3% vs 17.7%; moderate: 21.5% vs 33.1%; dementia: 0.0% vs 10.0%; p < 0.001). Patients undergoing STN DBS had a worse decline in overall cognitive status than patients who underwent GPI DBS (p = 0.006). Postoperative cognitive decline was associated with a more medial electrode position only for patients who underwent STN DBS. Cognitive change was observed in some patients with PD who underwent both GPI and STN DBS, likely due partly to underlying disease progression. Compared with GPI DBS, STN DBS was associated with a greater likelihood of cognitive decline. In STN but not GPI DBS, cognitive decline was associated with medialized electrode position, suggesting modulation of nonmotor STN divisions may contribute to cognitive changes following STN DBS.

In the article “Deep brain stimulation improves restless legs syndrome in patients with Parkinson disease,” Dr. Klepitskaya et al. reported sustained improvement in symptoms of restless legs syndrome (RLS) over 2 years in 22 patients with Parkinson disease (PD) who underwent subthalamic nucleus (STN) deep brain stimulation (DBS), despite a decrease in dopaminergic treatment. Drs. Marques et al. point out that the article misinterpreted the results of their previous study, which showed an emergence of RLS in patients with PD with a higher dose of dopamine agonists and a lower decrease in dopaminergic treatment after STN DBS. They discuss the paradoxical findings of STN DBS apparently improving preexisting RLS but causing emergence of RLS in some patients with PD and the need for further research. In response, Dr. Klepitskaya acknowledges these comments including the misinterpretation. A correction appears on page 871. In the article “Deep brain stimulation improves restless legs syndrome in patients with Parkinson disease,” Dr. Klepitskaya et al. reported sustained improvement in symptoms of restless legs syndrome (RLS) over 2 years in 22 patients with Parkinson disease (PD) who underwent subthalamic nucleus (STN) deep brain stimulation (DBS), despite a decrease in dopaminergic treatment. Drs. Marques et al. point out that the article misinterpreted the results of their previous study, which showed an emergence of RLS in patients with PD with a higher dose of dopamine agonists and a lower decrease in dopaminergic treatment after STN DBS.

SPECIALTY GRAND CHALLENGE article Front. Neurol., 24 May 2011Sec. Movement Disorders volume 2 - 2011 | https://doi.org/10.3389/fneur.2011.00033

Psychiatric and behavioral disorders may occur during Parkinson's disease (PD). Some are disease-related, such as depression and apathy. Others result from dopamine replacement therapy, notably two addictive disorders: impulse control disorder (ICD) and dopaminergic dysregulation syndrome (DDS). DDS is characterized by severe dopamine dependence, with patients compulsively abusing dopaminergic drugs despite disabling dyskinesia and mood lability. DDS looks very similar to the hedonic homeostatic dysregulation described in drug addiction. It is expressed as spiraling cycles of dysregulation of the brain's reward systems, gradually increasing and culminating in compulsive drug use and loss of control over drug-taking. The efficacy of subthalamic nucleus (STN) deep brain stimulation (DBS) on PD's motor symptoms is undebated, but its effects on cognitive and motivational troubles are more debated. Regarding the impact of STN-DBS on DDS and ICD, while some authors have reported none or negative effects, others have reported positive outcomes after STN-DBS.1-3 The beneficial effects are in line with preclinical studies in rats showing beneficial effect of STN inhibition or DBS on rat's model of the various criteria of addiction, leading to suggest STN DBS as a treatment for drug addiction, and especially cocaine.4-6 Here, we report a good outcome after bilateral STN-DBS on a PD patient with DDS and cocaine addiction. Written informed consent to publish details of the case was obtained from the patient. A 58-year-old man with an 8-year history of PD underwent STN-DBS for severe dyskinesia. This patient had a 20-year history of severe cocaine addiction (2 to 3 g per month). He took no other illicit substances but was an active smoker (one pack every 3 days for 20 years). Two years before STN-DBS, he presented with an ICD induced by Pramipexole LP (4.2 mg). This ICD combined hypersexuality, compulsive buying and gambling. With the withdrawal of Praxmipexole and adaptation of L-dopa, the patient presented a complete resolution of the DCI. He also presented a DDS and consumed more than 2500 mg of L-dopa per day. This DDS caused him psychomotor agitation, labile mood and severe dyskinesia impairing his autonomy, and his work as an electrician. Since STN-DBS implantation, he has never used cocaine again. He initially reported a few cravings, but for the first time he was able to resist them. However, his smoking habit continued. A few months after surgery, the patient's DDS was improved markedly, and his daily L-dopa dose decreased to 1000 mg. The patient's motor score remained improved. However, he developed apathy and a mild depressive state. Low-dose Pramipexole (0.52 mg) was reintroduced but was ineffective. We assessed this apathy 1 year after STN-DBS by a specific score, using the Starkstein scale. With a score of 23/42 for a threshold of 14, it confirmed an apathetic state. The French Dimensional Apathy score was applied to characterize this, and only the Initiation score was significant. He has never again exhibited any form of ICD. His quality of life remained improved. Table 1 summarized the clinical features. STN-DBS significantly improved the patient's DDS and cocaine addiction. Some authors have already reported the possible positive effect of STN-DBS on DDS.2, 3 Several mechanisms may underlie these effects, which are not exclusive to dopamine addiction. Evidence from animal studies suggests that STN activity is implicated in vulnerability to cocaine.6 Follow-up studies have demonstrated a notable impact of STN-DBS in rodents, and more recently, in a human case report.4, 6, 7 The involvement of the STN's connections with the reward system could explain some of these results. Inhibition of neural circuits resulting from STN-DBS may have affected direct and ascending dopaminergic and serotonergic pathways to the limbic area. Via the nucleus accumbens, these pathways play an important role in mediating reward-seeking effects and contribute significantly to the positive reinforcing effects of drug abuse. These effects were followed by a severe apathy related to an auto-activation deficit; executive functions were preserved. Post-STB-DBS apathy has been reported as an adverse effect in parkinsonian patients, but its mechanisms are still not fully understood. It could be explained by the reduced availability of mesolimbic and mesocortical dopamine secondary to the postoperative reduction in dopamine therapy.8 This behavior has not been described in the aftermath of case-report surgery.7 It is however in line with the functional involvement of STN in emotional processes reported in rodents and the electrophysiological delimitation of the emotional STN in PD patients.9, 10 Thus, we report here a second case of a cocaine-addicted patient, totally abstinent since STNS-DBS. Dopamine dependence also completely resolved. This reinforces the idea that STN may be a valid candidate target in the treatment with DBS of certain forms of addiction. The authors declare no conflict of interest.

Deep brain stimulation and refractory freezing of gait in Parkinson’s disease: Improvement with high-frequency current steering co-stimulation of subthalamic nucleus and substantia Nigra

Do patient's get angrier following STN, GPi, and thalamic deep brain stimulation

Concern about cognitive worsening, especially after subthalamic nucleus (STN) deep brain stimulation (DBS) has been reported in Parkinson’s disease (PD) patients, although it has not been deemed severe enough to discredit DBS as a powerful tool in the armamentarium against PD. We here provide an in-depth and critical review of the current literature on this topic, summarizing the available data on the impact of STN and globus pallidus interna (GPi) DBS on each of the following cognitive domains: language, executive function, attention and concentration, memory, visual function, psychomotor and processing speed, and global cognition; then looking in more details into controlled studies as well as studies directly comparing GPi and STN DBS. We conclude that worsening of one or more cognitive function is rare and subtle after DBS in PD patients, without negative impact on quality of life, and that there is very little data supporting that STN DBS has a worse cognitive outcome than Gpi DBS.

I. Overview of Deep Brain Stimulation 1. Functional anatomy and physiology of the basal ganglia: Motor functions Yoland Smith PhD, Thomas Wichmann MD 2. Functional anatomy and physiology of the basal ganglia: Non-motor functions Suzanne N Haber PhD 3. History of the therapeutic use of electricity on the brain and the development of deep brain stimulation Matthew A Butler MD, Joshua M Rosenow MD, Michael S Okun MD 4. Deep brain stimulation: Patient selection in Parkinson's disease, other movement disorders, and neuropsychiatric disorders. Mustafa S Siddiqui MD, Thomas Ellis MD, Stephen S Tatter MD, PhD, Kelly D Foote MD, Michael S Okun MD 5. Technical alternatives in performing deep brain stimulation implantation Paul S Larson MD 6. Microelectrode mapping in DBS Frank Steigerwald MD, Jens Volkmann MD 7. Complication avoidance and management in deep brain stimulation surgery Philip A Starr MD, PhD, Karl Sillay MD Mechanisms of Deep Brain Stimulation Svjetlana Miocinovic PhD, Cameron C. McIntyre PhD, Mark Sylvasta PhD, Jerrold L Vitek PhD, MD Functional imaging of deep brain stimulation: fMRI versus SPECT and PET Robert Jech MD, PhD II. Deep Brain Stimulation in Movement Disorders 10. Thalamic Deep brain Stimulation and essential tremor Kelly E Lyons PhD, Rajesh Pahwa MD 11. Thalamic deep brain stimulation for other tremors Erwin B Montgomery MD 12.Thalamic deep brain stimulation for Parkinson's disease tremor Daniel Tarsy MD, Efstathios Papavassiliou MD, Kelly E Lyons PhD, Rajesh Pahwa MD 13. Globus Pallidus deep brain stimulation for Parkinson's disease Frances Weaver PhD Kenneth Follett MD, PhD, Matthew Stern MD 14. Subthalamic nucleus deep brain stimulation for Parkinson's disease Marcelo Merello MD, PhD 15. Subthalamic nucleus vs globus pallidus deep brain stimulation in Parkinson's disease Jorge Guridi MD, PhD, MC Rodriguez-Oroz MD, PhD, Jose A Obeso MD, PhD 16. Deep brain stimulation in atypical parkinsonism Ludy Shih MD, Daniel Tarsy, MD 17. Deep brain stimulation in dystonia Marie Vidailhet MD, PhD , David Grabli MD, Emmanuel Roze MD 18. Deep brain stimulation in Tourette syndrome Linda AckermansMD, Yasin Temel MD, PhD, Veerle Visser-Vandewalle MD, PhD 19. Deep brain stimulation and postural disturbance Helen Bronte-Stuart, MD, MSE III. Postoperative Management in Patients Undergoing Deep brain stimulation 20. Deep brain stimulation programming Ioannis Isaias MD, Michele Tagliati MD 21. Neuropsychological issues in deep brain stimulation for neurological and psychiatric disorders Alexander I Troster PhD, April B McTaggart BS, Ina A Heber DipIPsych 22. Deep brain stimulation safety (MRI and other electromagnetic interactions) Kenneth B Baker PhD , Michael B Phillips MD 23. Deep brain stimulation fault testing Jay L Shils PhD, Ron L

Background: Weight gain has been described in Parkinson’s disease (PD) patients after subthalamic nucleus (STN) deep brain stimulation (DBS). Objectives: We examined change in weight following DBS in both PD and dystonia patients to further investigate the role of disease and brain target (STN or globus pallidus internus, GPi) specificity. Methods: Data was retrospectively collected on 61 PD DBS patients (STN n = 31 or GPi n = 30) and on 36 dystonia DBS patients (STN n = 9 and GPi n = 27) before and after surgery. Annual change in body mass index (BMI) was evaluated with nonparametric tests between groups and multiple quantile regression. Results: PD patients treated with STN DBS had a small increase in median BMI while those with GPi had a small decrease in BMI. Dystonia patients treated with STN DBS had a greater increase in BMI per year compared to those treated with GPi DBS. Multivariable regression analyses for each disease showed little difference between targets in weight gain in those with PD, but STN target was strongly associated with weight gain in dystonia patients (STN vs. GPi, +7.99 kg, p = 0.012). Conclusions: Our results support previous reports of weight gain after DBS in PD. This is the first report to suggest a target-specific increase in weight following STN DBS in dystonia patients.

To compare the effects of subthalamic nucleus (STN) and globus pallidus interna (GPi) deep brain stimulation (DBS) on the motor outcome, gait and balance function, fall risk (FR), and non-motor symptoms in patients with advanced Parkinson's disease (PD). We randomized patients with advanced PD with the indication of DBS to undergo either STN or GPi DBS and followed them for 2 years. We collected data at baseline and postoperative 6, 12, and 24 months. We compared changes in the Unified Parkinson's Disease Rating Scale (UPDRS) score, timed gait tests, posturography, non-motor symptom questionnaire (NMSQuest), hospital anxiety and depression (HAD) scale, and levodopa equivalent dose (LED). We enrolled and randomized 12 patients to receive either STN (n = 6) or GPi (n = 6) DBS. Postoperative motor outcomes were significantly improved in both groups (p < 0.05). In both groups, timed gait tests exhibited better performance in mobility; however, patients receiving GPi DBS performed better than those receiving STN DBS in the timed gait tests (p < 0.05). Furthermore, the posturographic evaluation demonstrated a significant elevation in the FR in the STN group (p < 0.05). Both STN and GPi DBS are equally effective in alleviating disabling motor complications. However, seemingly, STN DBS could cause more gait and balance problems; hence, a tailored approach seems to be more appropriate in the target selection.