Left Subthalamic Nucleus Research Articles

Machine learning explains response variability of deep brain stimulation on Parkinson’s disease quality of life

Improving health-related quality of life (QoL) is crucial for managing Parkinson’s disease. However, QoL outcomes after deep brain stimulation (DBS) of the subthalamic nucleus (STN) vary considerably. Current approaches lack integration of demographic, patient-reported, neuroimaging, and neurophysiological data to understand this variability. This study used explainable machine learning to analyze multimodal factors affecting QoL changes, measured by the Parkinson’s Disease Questionnaire (PDQ-39) in 63 patients, and quantified each variable’s contribution. Results showed that preoperative PDQ-39 scores and upper beta band activity (>20 Hz) in the left STN were key predictors of QoL changes. Lower initial QoL burden predicted worsening, while improvement was associated with higher beta activity. Additionally, electrode positions along the superior-inferior axis, especially relative to the z = −7 coordinate in standard space, influenced outcomes, with improved and worsened QoL above and below this marker. This study emphasizes a tailored, data-informed approach to optimize DBS treatment and improve patient QoL.

Subthalamic nucleus neurons encode syllable sequence and phonetic characteristics during speech.

Speech is a complex behavior that can be used to study unique contributions of the basal ganglia to motor control in the human brain. Computational models suggest that the basal ganglia encode either the phonetic content or the sequence of speech elements. To explore this question, we investigated the relationship between phoneme and sequence features of a spoken syllable triplet and the firing rate of subthalamic nucleus (STN) neurons recorded during the implantation of deep brain stimulation (DBS) electrodes in individuals with Parkinson's disease. Patients repeated aloud a random sequence of three consonant-vowel (CV) syllables in response to audio cues. Single-unit extracellular potentials were sampled from the sensorimotor STN; a total of 227 unit recordings were obtained from the left STN of 25 subjects (4 females). Of these, 113 (50%) units showed significant task-related increased firing and 53 (23%) showed decreased firing (t test relative to inter-trial period baseline, P < 0.05). Linear regression analysis revealed that both populations of STN neurons encode phoneme and sequence features of produced speech. Maximal phoneme encoding occurred at the time of phoneme production, suggesting efference copy- or sensory-related processing, rather than speech motor planning (-50 ms and +175 ms relative to CV transition for consonant and vowel encoding, respectively). These findings demonstrate that involvement of the basal ganglia in speaking includes separate single unit representations of speech sequencing and phoneme selection in the STN.NEW & NOTEWORTHY Speech is a unique human behavior that requires dynamic execution of precisely timed and coordinated movements, resulting in intelligible vocalizations. Here, we demonstrate that activity of individual neurons in the subthalamic nucleus (STN) of the basal ganglia encode syllable sequence order and phoneme identity during a speech production task. These findings advance our understanding of neural substrates of human speech and shed light on potential involvement of the STN in complex human behaviors.

Unveiling the Dominant Factors in Subthalamic Stimulation for Improving Depression in Parkinson's Disease.

Currently, the conclusions of studies on subthalamic nucleus (STN) deep brain stimulation (DBS) for improving Parkinson's disease (PD) with depression are inconsistent, and the reasons for improvement or deterioration remain unclear. The aim was to investigate the prognosis of PD with depression after bilateral STN-DBS and the factors related to the improvement in depression. The local and network effects of DBS on depression in PD (DPD) were further explored based on the volume of tissue activation (VTA). The study analyzed 80 primary PD patients who had undergone bilateral STN-DBS, comprising 47 patients with improved depression and 33 patients without improvement. Two groups of clinical profiles and stimulation parameters were compared, and the network models for improving depression were constructed. The improvement in depression was closely associated with improvement in anxiety (odd rate [OR] = 1.067, P = 0.006) and the standardized space left y-coordinate (OR = 0.253, P = 0.005). The VTA overlapping with the left motor STN subregion is most significantly associated with improvement in depression (RSpearman = 0.53, P < 0.001; RPearson = 0.43, P < 0.001). The y-coordinates in the improvement group were closer to the optimal stimulation site for improving motor symptoms. Finally, both the structural and functional network models indicate a positive correlation between depression improvement and the connectivity of the sensorimotor cortex. The amelioration of DPD is primarily attributed to the stimulation of bilateral motor STN, particularly on the left. However, this stimulatory effect manifests as an indirect influence.

The causal role of the subthalamic nucleus in the inhibitory network.

The neural network mediating successful response inhibition mainly includes right hemisphere activation of the pre-supplementary motor area, inferior frontal gyrus (IFG), subthalamic nucleus (STN), and caudate nucleus. However, the causal role of these regions in the inhibitory network is undefined. Five patients with Parkinson's disease were assessed prior to and after therapeutic thermal ablation of the right STN in two separate functional magnetic resonance imaging (fMRI) sessions while performing a stop-signal task. Initiation times were faster but motor inhibition with the left hand (contralateral to the lesion) was significantly impaired as evident in prolonged stop-signal reaction times. Reduced inhibition after right subthalamotomy was associated (during successful inhibition) with the recruitment of basal ganglia regions outside the established inhibitory network. They included the putamen and caudate together with the anterior cingulate cortex and IFG of the left hemisphere. Subsequent network connectivity analysis (with the seed over the nonlesioned left STN) revealed a new inhibitory network after right subthalamotomies. Our results highlight the causal role of the right STN in the neural network for motor inhibition and the possible basal ganglia mechanisms for compensation upon losing a key node of the inhibition network.

Quantitative susceptibility mapping in amyotrophic lateral sclerosis: automatic quantification of the magnetic susceptibility in the subcortical nuclei

Objective: Previous studies have suggested a link between dysregulation of cortical iron levels and neuronal loss in amyotrophic lateral sclerosis (ALS) patients. However, few studies have reported differences in quantitative susceptibility mapping (QSM) values in subcortical nuclei between patients with ALS and healthy controls (HCs). Methods: MRI was performed using a 3 Tesla Prisma scanner (64-channel head coil), including 3D T1-MPRAGE and multi-echo 3D GRE for QSM reconstruction. Automated QSM segmentation was used to measure susceptibility values in the subcortical nuclei, which were compared between the groups. Correlations with clinical scales were analyzed. Group comparisons were performed using independent t-tests, with p < 0.05 considered significant. Correlations were assessed using Pearson’s correlation, with p < 0.05 considered significant. Cohen’s d was reported to compare the standardized mean difference (SMD) of QSM. Results: Twelve patients with limb-onset ALS (mean age 48.7 years, 75% male) and 13 age-, sex-, and handedness-matched HCs (mean age 44.6 years, 69% male) were included. Compared to HCs, ALS patients demonstrated significantly lower susceptibility in the left caudate nucleus (CN) (SMD = −0.845), right CN (SMD = −0.851), whole CN (SMD = −1.016), and left subthalamic nucleus (STN) (SMD = −1.000). Susceptibility in the left putamen (SMD = −0.857), left thalamus (SMD = −1.081), and whole thalamus (SMD = −0.968) was significantly higher in the patients. The susceptibility of the substantia nigra (SN), CN, and pulvinar was positively correlated with disease duration. Conclusions: QSM detects abnormal iron accumulation patterns in the subcortical gray matter of ALS patients, which correlates with disease characteristics, supporting its potential as a neuroimaging biomarker.

H - 57 Case Study: Chinese Older Adult with Parkinson Disease and Visual Impairment Presenting for Pre-Deep Brain Stimulation Evaluation.

We present a case in which intersecting linguistic and disability factors necessitated a flexible, qualitative approach to clinical decision making in the context of pre-deep brain stimulation (DBS) evaluation. LZ is a 70-year-old, right-handed, cisgender, Chinese male with history of Parkinson disease (PD) presenting for DBS evaluation. Symptoms included right extremity tremor with decreased effectiveness from dopamine therapy. Cognitive, behavioral, personality, or functional changes were denied. He had severe visual impairment due to macular degeneration and cataracts. LZ immigrated to the U.S. 30years prior and obtained a Ph.D. in Law. His English was not at the level of native speaker, but he declined use of an interpreter. Nevertheless, English proficiency was adequate to conduct testing. LZ's premorbid functioning was estimated as average. Scores on attention/working memory and verbal fluency were intact. Processing speed and auditory naming were below average. Memory performance was characterized by inefficient learning and intact recall. Executive functions were variable in verbal set switching and motor sequencing was intact. Typically, such a case with language/cultural differences would rely on more visuospatial than verbal tests; however, visual impairment necessitated reliance on verbal tests only. It was determined that variability of performances and low scores on naming were more likely attributable to language/cultural factors, and LZ was therefore deemed a good candidate for DBS surgery based on multiple intact cognitive abilities and strong social support. LZ received left subthalamic nucleus DBS. There was initial hemorrhagic complication during electrode placement resulting in language loss, which he recovered after five weeks.

Abnormal magnetic resonance imaging signal in the burr hole and the identification of the intracranial infection of a deep brain stimulation device: illustrative case.

Device infection is a critical postoperative complication in deep brain stimulation (DBS). However, intracranial infections are rare and lack specific findings, which lead to a challenging diagnosis. A 59-year-old female with generalized dystonia underwent bilateral globus pallidus internus and subthalamic nucleus (STN) DBS device implantation. One year earlier, a left STN-DBS extension wire disconnection was observed and replaced. The patient presented to our department because of tenderness along the extension wire that had persisted for 1 month. Magnetic resonance imaging (MRI) of the head indicated abnormal signals around the lead of the left STN and burr hole. Intraoperatively, the authors observed pus and infected granulation tissue in the burr holes. After device removal, antibiotics were administered, and the patient successfully progressed without complications. Moreover, the abnormal MRI signal disappeared. A characteristic abnormal MRI signal within the burr hole in DBS may suggest early infection even in the absence of other inflammatory findings. Clinicians should ensure that MRI is not limited to intracranial findings but extends beyond the extracranial space.

Clinical and Pathological Characterization of VPS16 Dystonia (P11-11.005)

<h3>Objective:</h3> To expand the clinical, radiologic and pathologic understanding of VPS16 related dystonia. <h3>Background:</h3> Variants in VPS16 have been associated with isolated dystonia in 35 cases from Chinese and European cohorts, including report of brainstem signal change on MRI. <h3>Design/Methods:</h3> We describe clinical features in 10 additional individuals with isolated dystonia and VPS16 variants, including neuroimaging on a subset and pathology in one, and perform pooled analysis with published cases. <h3>Results:</h3> 80% were men, mean age onset was 14.1 years (range 5–30), and mean age at exam was 35.89 years (range 11–73). Four began with arm, 3 with leg, and 3 with neck dystonia. Only one remained focal (arm); others became generalized (7), multifocal (1) or segmental (1). Brachial involvement was present in 90%, with 80% crural, 70% cranial/bulbar, and 50% cervical involvement. Two individuals underwent deep brain stimulation and one thalamotomy. Four cases were related, and five others had family history. MRI was available in two cases and demonstrated red nucleus and cerebral peduncle T2 hypointensity. Neuropathologic evaluation in one case (post bilateral GPi DBS) demonstrated asymmetric severe gliosis and marked neuronal loss of the left subthalamic nucleus with optically empty vacuoles and much less right-sided involvement. Pooled analysis with 34 additional published cases showed 62.22% male and average onset of 14.53 years (range 3–50). Onset site was 20.45% cranial/bulbar, 54.55% limb, and 36.36% axial (cervical or trunk); 75% of cases exhibited cranial/bulbar symptoms, 90.9% limb and 81.82% axial involvement. <h3>Conclusions:</h3> Expansion of known cases of VPS16 dystonia further support that it is a childhood-or adolescent-onset disorder, typically with limb or cervical onset that often spreads to the arm and leg. Additional histopathologic and metabolomic evaluation is underway to better understand the lysosomal and endolysosomal pathophysiology that may contribute to both vacuolization in the subthalamic nucleus as well as T2 brainstem hypointensities. <b>Disclosure:</b> The institution of Dr. Pullman has received research support from Empire Clinical Research Investigator Program. The institution of Ms. Raymond has received research support from NIH. Dr. Molofsky has nothing to disclose. Dr. Lubarr has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for applied therapeutics. Dr. Leaver has nothing to disclose. Roberto Ortega has nothing to disclose. Ms. Rawal has nothing to disclose. The institution of Dr. Bennett has received research support from Prevail. Mr. Bushnik has nothing to disclose. Dr. Khorsandi has nothing to disclose. Fedor Panov has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for neuropace. Fedor Panov has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for zimmer biomet. Jean Paul Vonsattel has nothing to disclose. The institution of Dr. Ozelius has received research support from NIH. Dr. Ozelius has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Saunders-Pullman has received research support from NIH, Bigglesworth Family Foundation, Empire Clinical Research Investigatory Program. The institution of Dr. Bressman has received research support from Michael J Fox Foundation . The institution of Dr. Bressman has received research support from NIH .

18F]PI‐2620 PET in four‐repeat tauopathies: a preliminary study

AbstractBackgroundThere is a critical need for tau PET radiotracers that accurately detect non‐Alzheimer’s disease (AD) tau pathology. We aim to evaluate [18F]PI‐2620 PET tracer retention in patients with non‐AD, 4R tau‐related clinical syndromes, including progressive supranuclear palsy (PSP) with Richardson’s syndrome (PSP‐RS) and with predominant parkinsonism (PSP‐P), corticobasal syndrome (CBS), and nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA).Method38 participants underwent amyloid and [18F]PI‐2620 PET (Table 1). 5 mCi ± 10% of [18F]PI‐2620 was administered. [18F]PI‐2620 PET SUVR images were generated using an inferior cerebellar gray matter reference from PET data acquired 30‐60 minutes post‐injection. Mean SUVR values were extracted from each participant in neuroanatomical structures that have elevated tau burden in PSP and CBS due to corticobasal degeneration (regions of interest in Table 2). Comparison between each diagnostic group and healthy controls (HCs) was performed using a one‐tailed, independent‐samples t‐test. Spearman correlation was used to evaluate the relationship between tracer binding (SUVR) and disease severity (PSP rating scale) in patients with PSP‐RS.ResultPatients with PSP‐RS had increased tracer retention in the left globus pallidus internus and externus, left subthalamic nucleus, and left dorsolateral prefrontal cortex compared to HCs (all p &lt; 0.05). CBS and nfvPPA patients did not have increased tracer retention at any ROIs compared to HCs, but there were low numbers of patients in these groups (Table 2, Figures 1‐3). PSP rating scale values did not correlate with tracer binding in PSP‐RS (no correlations in any regions, rs &lt; 0.44, p &gt; 0.05 uncorrected).Conclusion[18F]PI‐2620 PET 30‐60 minute SUVR images may have limited ability to distinguish PSP from HCs, especially on visual read, and tracer uptake did not correlate with PSP disease severity. Other post‐injection PET acquisition windows (e.g., 30‐40 minute SUVR, 0‐60 minute DVR) will be evaluated to determine if they can maximize differences between PSP and HCs. A limitation of this preliminary study is the modest number of patients and controls, with most controls provided from a different study. Additional participants are being scanned in the multicenter 4RTNI study to understand the utility of this tracer as a neuroimaging biomarker for 4R tauopathies.

Subthalamic Oscillatory Activity of Reward and Loss Processing Using the Monetary Incentive Delay Task in Parkinson Disease

BackgroundThe subthalamic nucleus (STN) is an effective deep brain stimulation target for Parkinson disease (PD) and obsessive-compulsive disorder and has been implicated in reward and motivational processing. In this study, we assessed the STN and prefrontal oscillatory dynamics in the anticipation and receipt of reward and loss using a task commonly used in imaging. Materials and MethodsWe recorded intracranial left subthalamic local field potentials from deep brain stimulation electrodes and prefrontal scalp electroencephalography in 17 patients with PD while they performed a monetary incentive delay task. ResultsDuring the expectation phase, enhanced left STN delta-theta activity was observed in both reward and loss vs neutral anticipation, with greater STN delta-theta activity associated with greater motivation specifically to reward. In the consummatory outcome phase, greater left STN delta activity was associated with a rewarding vs neutral outcome, particularly with more ventral contacts along with greater delta-theta coherence with the prefrontal cortex. We highlight a differential activity in the left STN to loss vs reward anticipation, demonstrating a distinct STN high gamma activity. Patients with addiction-like behaviors show lower left STN delta-theta activity to loss vs neutral outcomes, emphasizing impaired sensitivity to negative outcomes. ConclusionsTogether, our findings highlight a role for the left STN in reward and loss processing and a potential role in addictive behaviors. These findings emphasize the cognitive-limbic function of the STN and its role as a physiologic target for neuropsychiatric disorders.

The Fundamental Basis of Palpitations: A Neurocardiology Approach.

Palpitations are a common symptom that may indicate cardiac arrhythmias, be a somatic complaint in anxiety disorders, and can be present in patients without either condition. The objective of this review was to explore the pathways and fundamental mechanisms through which individuals appreciate palpitations. Cardiac afferents provide beat-to-beat sensory information on the heart to the spinal cord, brain stem, and higher brain centers. Cardioception, a subset of interoception ('the physiological sense of the condition of the body'), refers to sensing of the heartbeat. High cardioception is present in persons with lower body mass index, lower percentages of body fat, and anxiety disorders. Low cardioception (lower interoceptive awareness) is associated with psychiatric disorders, such as depression, personality disorders, and schizophrenia. CNS sites associated with heartbeat detection have been identified by functional magnetic resonance imaging studies and heartbeat-evoked electroencephalogram potentials. The right insula, cingulate gyrus, somatomotor and somatosensory cortices nucleus accumbens, left subthalamic nucleus, and left ventral capsule/striatum are implicated in both palpitations and heartbeat detection. Involvement of the brain as a primary modulator of palpitations rests on the data that various areas of the brain are activated in association with cardioception, the ability of focal brain stimulation to induce palpitations, the ability of central alpha receptor agonists and antagonists to modulate palpitations, and suppression of palpitations by transcranial repetitive magnetic stimulation (rTMS). Palpitations should be viewed as a pathway extending from the heart to the brain. Palpitations are, in part, a reflection of an individual's cardioception awareness, which is modulated by body size, percentage of body fat, and psychological or psychiatric conditions. Palpitations can originate in the brain and involve central neurotransmitters. Treatment of palpitations unrelated to cardiac arrhythmias or anxiety disorders should consider the use of central alpha-2 agonists and possibly rTMS.

Consistent Changes in Cortico-Subthalamic Directed Connectivity Are Associated With the Induction of Parkinsonism in a Chronically Recorded Non-human Primate Model.

Parkinson’s disease is a neurological disease with cardinal motor signs including bradykinesia and tremor. Although beta-band hypersynchrony in the cortico-basal ganglia network is thought to contribute to disease manifestation, the resulting effects on network connectivity are unclear. We examined local field potentials from a non-human primate across the naïve, mild, and moderate disease states (model was asymmetric, left-hemispheric dominant) and probed power spectral density as well as cortico-cortical and cortico-subthalamic connectivity using both coherence and Granger causality, which measure undirected and directed effective connectivity, respectively. Our network included the left subthalamic nucleus (L-STN), bilateral primary motor cortices (L-M1, R-M1), and bilateral premotor cortices (L-PMC, R-PMC). Results showed two distinct peaks (Peak A at 5–20 Hz, Peak B at 25–45 Hz) across all analyses. Power and coherence analyses showed widespread increases in power and connectivity in both the Peak A and Peak B bands with disease progression. For Granger causality, increases in Peak B connectivity and decreases in Peak A connectivity were associated with the disease. Induction of mild disease was associated with several changes in connectivity: (1) the cortico-subthalamic connectivity in the descending direction (L-PMC to L-STN) decreased in the Peak A range while the reciprocal, ascending connectivity (L-STN to L-PMC) increased in the Peak B range; this may play a role in generating beta-band hypersynchrony in the cortex, (2) both L-M1 to L-PMC and R-M1 to R-PMC causalities increased, which may either be compensatory or a pathologic effect of disease, and (3) a decrease in connectivity occurred from the R-PMC to R-M1. The only significant change seen between mild and moderate disease was increased right cortical connectivity, which may reflect compensation for the left-hemispheric dominant moderate disease state.

The motor inhibitory network in patients with asymmetrical Parkinson’s disease: An fMRI study

Recent imaging studies with the stop-signal task in healthy individuals indicate that the subthalamic nucleus, the pre-supplementary motor area and the inferior frontal gyrus are key components of the right hemisphere “inhibitory network”. Limited information is available regarding neural substrates of inhibitory processing in patients with asymmetric Parkinson’s disease. The aim of the current fMRI study was to identify the neural changes underlying deficient inhibitory processing on the stop-signal task in patients with predominantly left-sided Parkinson’s disease. Fourteen patients and 23 healthy controls performed a stop-signal task with the left and right hands. Behaviorally, patients showed delayed response inhibition with either hand compared to controls. We found small imaging differences for the right hand, however for the more affected left hand when behavior was successfully inhibited we found reduced activation of the inferior frontal gyrus bilaterally and the insula. Using the stop-signal delay as regressor, contralateral underactivation in the right dorsolateral prefrontal cortex, inferior frontal and anterior putamen were found in patients. This finding indicates dysfunction of the right inhibitory network in left-sided Parkinson’s disease. Functional connectivity analysis of the left subthalamic nucleus showed a significant increase of connectivity with bilateral insula. In contrast, the right subthalamic nucleus showed increased connectivity with visuomotor and sensorimotor regions of the cerebellum. We conclude that altered inhibitory control in left-sided Parkinson’s disease is associated with reduced activation in regions dedicated to inhibition in healthy controls, which requires engagement of additional regions, not observed in controls, to successfully stop ongoing actions.

α and θ oscillations in the subthalamic nucleus are potential biomarkers for Parkinson's disease with depressive symptoms

IntroductionAbnormal α oscillations in the bed nucleus of stria terminalis and subgenual cingulate of patients with depression correlate with symptom severity. Some Parkinson's disease (PD) patients also have abnormal θ-α oscillations in the subthalamic nucleus (STN). However, the relationship between abnormal θ-α oscillations and depressive symptoms in PD patients has not been determined. This study explored the correlation between α and θ oscillations of the STN and depressive symptoms in PD patients. MethodsWe conducted a retrospective case-control study on 36 PD patients with (dPD group) or without depressive symptoms (nPD group), analyzing the difference in the average power spectral density (PSD) of α and θ oscillations of the local field potential (LFP) recorded in the STN during deep brain stimulation (DBS), and their correlation with the Hamilton depression rating scale (HAMD) of PD patients during the same period. ResultsThe dPD group had a higher PSD of α oscillations and a lower PSD of θ oscillations in the left ventral STN. The PSD of α oscillations of the left ventral STN were positively correlated with the severity of depressive symptoms, whereas the PSD of θ oscillations of this location was negatively correlated with severity of depressive symptoms. The PSD of α and θ oscillations did not correlate with motor symptoms, sleep quality, or quality of life score. ConclusionAbnormal α and θ oscillations of the left ventral STN could be used as biomarkers of PD with depressive symptoms, which might guide STN-DBS treatment.

P-MD004. Peak dose ballistic movements towards the implantable pulse generator life end in deep brain stimulation

Introduction . The objective of this case report is to highlight the unusual presentation of peak dose ballistic movements towards the end of the implantable pulse generator (IPG) life span in a patient with bilateral sub-thalamic nucleus (STN) deep brain stimulation (DBS). Results . We report a case of sudden severe peak dose ballistic movements and increased “off” periods in a PD patient with bilateral STN DBS towards the end life of the IPG despite a normal battery range according to the Medtronic Battery Status Indicator. The Unified Parkinson Disease Rating Scale III (UPDRS III) escalated by 12 points (from 63 to 75 points) with severe uncontrollable peak dose dyskinesia despite no medication adjustment. Stimulation settings were cut down to as low as 1.0 V on the left STN, and 1.5 V on the right STN at a frequency of 130 Hz and pulse width of 60 μs, yet the ballistic movements were still noticeable. The patient remained in “on” period with no dyskinesia throughout the day after replacement of the IPG with similar stimulation settings prior to the replacement of the IPG, with 2.1 V on the left STN, and 1.6 V on the right STN at a frequency of 130 Hz and pulse width of 60 μs. The patient’s UPDRS-III score was at 62 points after the replacement of IPG. Conclusion . We observed that the battery status indicator did not accurately predict the battery life of the IPG. Peak dose ballistic movements towards the end life of the IPG is an unusual presentation and could be an indicator of end life of the IPG in DBS.

Acute low frequency dorsal subthalamic nucleus stimulation improves verbal fluency in Parkinson's disease

BackgroundParkinson's disease (PD) is a common neurodegenerative disorder that results in movement-related dysfunction and has variable cognitive impairment. Deep brain stimulation (DBS) of the dorsal subthalamic nucleus (STN) has been shown to be effective in improving motor symptoms; however, cognitive impairment is often unchanged, and in some cases, worsened particularly on tasks of verbal fluency. Traditional DBS strategies use high frequency gamma stimulation for motor symptoms (∼130 Hz), but there is evidence that low frequency theta oscillations (5–12 Hz) are important in cognition. MethodsWe tested the effects of stimulation frequency and location on verbal fluency among patients who underwent STN DBS implantation with externalized leads. During baseline cognitive testing, STN field potentials were recorded and the individual patients’ peak theta frequency power was identified during each cognitive task. Patients repeated cognitive testing at five different stimulation settings: no stimulation, dorsal contact gamma (130 Hz), ventral contact gamma, dorsal theta (peak baseline theta) and ventral theta (peak baseline theta) frequency stimulation. ResultsAcute left dorsal peak theta frequency STN stimulation improves overall verbal fluency compared to no stimulation and to either dorsal or ventral gamma stimulation. Stratifying by type of verbal fluency probes, verbal fluency in episodic categories was improved with dorsal theta stimulation compared to all other conditions, while there were no differences between stimulation conditions in non-episodic probe conditions. ConclusionHere, we provide evidence that dorsal STN theta stimulation may improve verbal fluency, suggesting a potential possibility of integrating theta stimulation into current DBS paradigms to improve cognitive outcomes.

The Accuracy of Direct Targeting Using Fusion of MR and CT Imaging for Deep Brain Stimulation of the Subthalamic Nucleus in Patients with Parkinson's Disease.

In 33 consecutive patients with Parkinson's disease (PD) undergoing awake deep brain stimulation (DBS) without microelectrode recording (MER), we assessed and validated the precision and accuracy of direct targeting of the subthalamic nucleus (STN) using preoperative magnetic resonance imaging (MRI) and stereotactic computed tomography (CT) image fusion combined with immediate postoperative stereotactic CT and postoperative MRI, and we report on the side effects and clinical results up to 6 months' follow-up. Preoperative nonstereotactic MRI and stereotactic CT images were merged and used for planning the trajectory and final lead position. Immediate postoperative stereotactic CT and postoperative nonstereotactic MRI provided the validation of the final electrode position. Changes in the Unified Parkinson's Disease Rating Scale III (UPDRS III) scores and the levodopa equivalent daily doses (LEDD) and appearance of adverse side effects were assessed. The mean Euclidian distance (ED) error between the planned position and the final position of the lead in the left STN was 1.69 ± 0.82 mm and that in the right STN was 2.12 ± 1.00. The individual differences between planned and final position in each of the three coordinates were less than 2 mm. The UPDRS III scores improved by 75% and LEDD decreased by 45%. Few patients experienced complications, such as postoperative infection (n = 1), or unwanted side effects, such as emotional instability (n = 1). Our results confirm that direct targeting of an STN on stereotactic CT merged with MRI could be a valid method for placement the DBS electrode. The magnitude of our targeting error is comparable with the reported errors when using MER and other direct targeting approaches.

Deep brain stimulation effects on verbal fluency dissociated by target and active contact location.

ObjectiveDeep brain stimulation (DBS) improves motor symptoms in Parkinson’s disease (PD), but it can also disrupt verbal fluency with significant costs to quality of life. The current study investigated how variability of bilateral active electrode coordinates along the superior/inferior, anterior/posterior, and lateral/medial axes in the subthalamic nucleus (STN) or the globus pallidus interna (GPi) contribute to changes in verbal fluency. We predicted that electrode location in the left hemisphere would be linked to changes in fluency, especially in the STN.MethodsForty PD participants treated with bilateral DBS targeting STN (n = 23) or GPi (n = 17) completed verbal fluency testing in their optimally treated state before and after DBS therapy. Normalized atlas coordinates from left and right active electrode positions along superior/inferior, anterior/posterior, and lateral/medial axes were used to predict changes in fluency postoperatively, separately for patients with STN and GPi targets.ResultsConsistent with prior studies, fluency significantly declined pre‐ to postsurgery (in both DBS targets). In STN‐DBS patients, electrode position along the inferior to superior axis in the left STN was a significant predictor of fluency changes; relatively more superior left active electrode was associated with the largest fluency declines in STN. Electrode coordinates in right STN or GPi (left or right) did not predict fluency changes.InterpretationWe discuss these findings in light of putative mechanisms and potential clinical impact.

Resting-State Phase-Amplitude Coupling Between the Human Subthalamic Nucleus and Cortical Activity: A Simultaneous Intracranial and Scalp EEG Study.

It has been suggested that slow oscillations in the subthalamic nucleus (STN) reflect top-down inputs from the medial prefrontal cortex, thus implementing behavior control. It is unclear, however, whether the STN oscillations are related to cortical activity in a bottom-up manner. To assess resting-state subcortico-cortical interactions, we recorded simultaneous scalp electroencephalographic activity and local field potentials in the STN (LFP-STN) in 11 patients with Parkinson's disease implanted with deep brain stimulation electrodes in the on-medication state during rest. We assessed the cross-structural phase-amplitude coupling (PAC) between the STN and cortical activity within a wide frequency range of 1 to 100Hz. The PAC was dominant between the δ/θ STN phase and β/γ cortical amplitude in most investigated scalp regions and between the δ cortical phase and θ/α STN amplitude in the frontal and temporal regions. The cross-frequency linkage between the slow oscillations of the LFP-STN activity and the amplitude of the scalp-recorded cortical activity at rest was demonstrated, and similar involvement of the left and right STNs in the coupling was observed. Our results suggest that the STN plays a role in both bottom-up and top-down processes within the subcortico-cortical circuitries of the human brain during the resting state. A relative left-right symmetry in the STN-cortex functional linkage was suggested. Practical treatment studies would be necessary to assess whether unilateral stimulation of the STN might be sufficient for treatment of Parkinson's disease.

Resting-State Functional Connectivity Predicts STN DBS Clinical Response.

Deep brain stimulation of the subthalamic nucleus is a widely used adjunctive therapy for motor symptoms of Parkinson's disease, but with variable motor response. Predicting motor response remains difficult, and novel approaches may improve surgical outcomes as well as the understanding of pathophysiological mechanisms. The objective of this study was to determine whether preoperative resting-state functional connectivity MRI predicts motor response from deep brain stimulation of the subthalamic nucleus. We collected preoperative resting-state functional MRI from 70 participants undergoing subthalamic nucleus deep brain stimulation. For this cohort, we analyzed the strength of STN functional connectivity with seeds determined by stimulation-induced (ON/OFF) 15 O H2 O PET regional cerebral blood flow differences in a partially overlapping group (n = 42). We correlated STN-seed functional connectivity strength with postoperative motor outcomes and applied linear regression to predict motor outcomes. Preoperative functional connectivity between the left subthalamic nucleus and the ipsilateral internal globus pallidus correlated with postsurgical motor outcomes (r = -0.39, P = 0.0007), with stronger preoperative functional connectivity relating to greater improvement. Left pallidal-subthalamic nucleus connectivity also predicted motor response to DBS after controlling for covariates. Preoperative pallidal-subthalamic nucleus resting-state functional connectivity predicts motor benefit from deep brain stimulation, although this should be validated prospectively before clinical application. These observations suggest that integrity of pallidal-subthalamic nucleus circuits may be critical to motor benefits from deep brain stimulation. © 2020 International Parkinson and Movement Disorder Society.