Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

BackgroundDeep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized.ObjectiveThe objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr).MethodsTwo microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for Parkinson's disease (PD). Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode.ResultsInhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .013). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p > .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation but not in SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003).InterpretationPersistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections.     

Electrophysiologic Evidence That Directional Deep Brain Stimulation Activates Distinct Neural Circuits in Patients With Parkinson Disease

ObjectivesDeep brain stimulation (DBS) delivered via multicontact leads implanted in the basal ganglia is an established therapy to treat Parkinson disease (PD). However, the different neural circuits that can be modulated through stimulation on different DBS contacts are poorly understood. Evidence shows that electrically stimulating the subthalamic nucleus (STN) causes a therapeutic effect through antidromic activation of the hyperdirect pathway—a monosynaptic connection from the cortex to the STN. Recent studies suggest that stimulating the substantia nigra pars reticulata (SNr) may improve gait. The advent of directional DBS leads now provides a spatially precise means to probe these neural circuits and better understand how DBS affects distinct neural networks.Materials and MethodsWe measured cortical evoked potentials (EPs) using electroencephalography (EEG) in response to low-frequency DBS using the different directional DBS contacts in eight patients with PD.ResultsA short-latency EP at 3 milliseconds originating from the primary motor cortex appeared largest in amplitude when stimulating DBS contacts closest to the dorsolateral STN (p < 0.001). A long-latency EP at 10 milliseconds originating from the premotor cortex appeared strongest for DBS contacts closest to the SNr (p < 0.0001).ConclusionsOur results show that at the individual patient level, electrical stimulation of different nuclei produces distinct EP signatures. Our approach could be used to identify the functional location of each DBS contact and thus help patient-specific DBS programming.Clinical Trial RegistrationThe ClinicalTrials.gov registration number for the study is NCT04658641.     

Correspondence of optimal stimulation and beta power varies regionally in STN DBS for Parkinson disease

IntroductionSubthalamic nucleus deep brain stimulation (STN DBS) for Parkinson disease (PD) normalizes neuronal hypersynchrony in the beta frequency range (13–30 Hz). The spatial correspondence of maximal beta power to the site of optimal stimulation along the DBS lead trajectory has been debated.MethodsWe determined the trajectory locations of the active contact, maximal beta power, and the dorsal border of the STN (DB-STN) in DBS patients. Beta power profiles were measured during intraoperative microelectrode recording (MER). Active contact locations were assigned during blinded, postoperative DBS programming. The DB-STN was identified both electrophysiologically during MER and anatomically on MRI. After grouping DBS trajectories into quadrants relative to the anatomic STN midpoint, we examined regional variations in the relative trajectory locations of the three entities.ResultsSTN DBS significantly improved motor performance for all 13 DBS patients, with active contacts at the DB-STN. Along trajectories passing posterior-medial to the STN midpoint, maximal beta power co-localized with active contacts at the DB-STN (difference Δ = 0.4 ± 1.6 mm, p = 0.57). By contrast, in posterior-lateral trajectories, maximal beta arose within the STN, ventral to active contacts (Δ = 1.9 ± 1.3 mm, p = 0.002). For trajectories anterior to the STN midpoint, maximal beta power co-localized with the DB-STN, while active contacts were ventral to peak beta power (p = 0.05).ConclusionOur findings indicate that co-localization of optimal stimulation and beta power varies by anatomical region in STN DBS for Parkinson disease.     

Deep Brain Stimulation and Levodopa Affect Gait Variability in Parkinson Disease Differently

BackgroundBoth dopaminergic medication and subthalamic nucleus (STN) deep brain stimulation (DBS) can improve the amplitude and speed of gait in Parkinson disease (PD), but relatively little is known about their comparative effects on gait variability. Gait irregularity has been linked to the degeneration of cholinergic neurons in the pedunculopontine nucleus (PPN).ObjectivesThe STN and PPN have reciprocal connections, and we hypothesized that STN DBS might improve gait variability by modulating PPN function. Dopaminergic medication should not do this, and we therefore sought to compare the effects of medication and STN DBS on gait variability.Materials and MethodsWe studied 11 patients with STN DBS systems on and off with no alteration to their medication, and 15 patients with PD without DBS systems on and off medication. Participants walked for two minutes in each state, wearing six inertial measurement units. Variability has previously often been expressed in terms of SD or coefficient of variation over a testing session, but these measures conflate long-term variability (eg, gradual slowing, which is not necessarily pathological) with short-term variability (true irregularity). We used Poincaré analysis to separate the short- and long-term variability.ResultsDBS decreased short-term variability in lower limb gait parameters, whereas medication did not have this effect. In contrast, STN DBS had no effect on arm swing and trunk motion variability, whereas medication increased them, without obvious dyskinesia.ConclusionsOur results suggest that STN DBS acts through a nondopaminergic mechanism to reduce gait variability. We believe that the most likely explanation is the retrograde activation of cholinergic PPN projection neurons.     

Acute Changes in Mood Induced by Subthalamic Deep Brain Stimulation in Parkinson Disease Are Modulated by Psychiatric Diagnosis

BackgroundDeep brain stimulation of the subthalamic nucleus (STN DBS) reduces Parkinson disease (PD) motor symptoms but has unexplained, variable effects on mood.ObjectiveThe study tested the hypothesis that pre-existing mood and/or anxiety disorders or increased symptom severity negatively affects mood response to STN DBS.MethodsThirty-eight PD participants with bilateral STN DBS and on PD medications were interviewed with Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) and completed Beck Depression Inventory (BDI) and Spielberger State Anxiety Inventory (SSAI) self-reports. Subsequently, during OFF and optimal ON (clinical settings) STN DBS conditions and while off PD medications, motor function was assessed with the United Parkinson Disease Rating Scale (UPDRS, part III), and participants rated their mood with Visual Analogue Scales (VAS), and again completed SSAI. VAS mood variables included anxiety, apathy, valence and emotional arousal.ResultsSTN DBS improved UPDRS scores and mood. Unexpectedly, PD participants diagnosed with current anxiety or mood disorders experienced greater STN DBS-induced improvement in mood than those diagnosed with remitted disorders or who were deemed as having never met threshold criteria for diagnosis. BDI and SSAI scores did not modulate mood response to STN DBS, indicating that clinical categorical diagnosis better differentiates mood response to STN DBS than self-rated symptom severity. SCID diagnosis, BDI and SSAI scores did not modulate motor response to STN DBS.ConclusionsPD participants diagnosed with current mood or anxiety disorders are more sensitive to STN DBS-induced effects on mood, possibly indicating altered basal ganglia circuitry in this group.     

Probabilistic Subthalamic Nucleus Stimulation Sweet Spot Integration Into a Commercial Deep Brain Stimulation Programming Software Can Predict Effective Stimulation Parameters

ObjectivesSubthalamic nucleus (STN) deep brain stimulation (DBS) programming in patients with Parkinson disease (PD) may be challenging, especially when using segmented leads. In this study, we integrated a previously validated probabilistic STN sweet spot into a commercially available software to evaluate its predictive value for clinically effective DBS programming.Materials and MethodsA total of 14 patients with PD undergoing bilateral STN DBS with segmented leads were included. A nonlinear co-registration of a previously defined probabilistic sweet spot onto the manually segmented STN was performed together with lead reconstruction and tractography of the corticospinal tract (CST) in each patient. Contacts were ranked (level and direction), and corresponding effect and side-effect thresholds were predicted based on the overlap of the volume of activated tissue (VTA) with the sweet spot and CST. Image-based findings were correlated with postoperative clinical testing results during monopolar contact review and chronic stimulation parameter settings used after 12 months.ResultsImage-based contact prediction showed high interrater reliability (Cohen kappa 0.851–0.91). Image-based and clinical ranking of the most efficient ring level and direction of stimulation were matched in 72% (95% CI 57.0–83.3) and 65% (95% CI 44.9–81.2), respectively, across the whole cohort. The mean difference between the predicted and clinically observed effect thresholds was 0.79 ± 0.69 mA (p = 0.72). The median difference between the predicted and clinically observed side-effect thresholds was ?0.5 mA (p < 0.001, Wilcoxon paired signed rank test).ConclusionsIntegration of a probabilistic STN functional sweet spot into a surgical programming software shows a promising capability to predict the best level and directional contact(s) as well as stimulation settings in DBS for PD and could be used to optimize programming with segmented lead technology. This integrated image-based programming approach still needs to be evaluated on a bigger data set and in a future prospective multicenter cohort.     

Effects of Contralateral Deep Brain Stimulation and Levodopa on Subthalamic Nucleus Oscillatory Activity and Phase-Amplitude Coupling

BackgroundThe modulatory effects of medication and deep brain stimulation (DBS) on subthalamic nucleus (STN) neural activity in Parkinson's disease have been widely studied. However, effects on the contralateral side to the stimulated STN, in particular, changes in local field potential (LFP) oscillatory activity and phase-amplitude coupling (PAC), have not yet been reported.ObjectiveThe aim of this study was to examine changes in STN LFP activity across a range of frequency bands and STN PAC for different combinations of DBS and medication on/off on the side contralateral to the applied stimulation.Materials and MethodsWe examined STN LFPs that were recorded using externalized leads from eight parkinsonian patients during unilateral DBS from the side contralateral to the stimulation. LFP spectral power in alpha (5 to ～13 Hz), low beta (13 to ～20 Hz), high beta (20–30 Hz), and high gamma plus high-frequency oscillation (high gamma+HFO) (100–400 Hz) bands were estimated for different combinations of medication and unilateral stimulation (off/on). PAC between beta and high gamma+HFO in the STN LFPs was also investigated. The effect of the condition was examined using linear mixed models.ResultsPAC in the STN LFP was reduced by DBS when compared to the baseline condition (no medication and stimulation). Medication had no significant effect on PAC. Alpha power decreased with DBS, both alone and when combined with medication. Beta power decreased with DBS, medication, and DBS and medication combined. High gamma+HFO power increased during the application of contralateral DBS and was unaltered by medication.ConclusionsThe results provide new insights into the effects of DBS and levodopa on STN LFP PAC and oscillatory activity on the side contralateral to stimulation. These may have important implications in understanding mechanisms underlying motor improvements with DBS, including changes on both contralateral and ipsilateral sides, while suggesting a possible role for contralateral sensing during unilateral DBS.     

Subthalamic Nucleus Deep Brain Stimulation Induces Motor Network BOLD Activation: Use of a High Precision MRI Guided Stereotactic System for Nonhuman Primates

BackgroundFunctional magnetic resonance imaging (fMRI) is a powerful method for identifying in vivo network activation evoked by deep brain stimulation (DBS).ObjectiveIdentify the global neural circuitry effect of subthalamic nucleus (STN) DBS in nonhuman primates (NHP).MethodAn in-house developed MR image-guided stereotactic targeting system delivered a mini-DBS stimulating electrode, and blood oxygenation level-dependent (BOLD) activation during STN DBS in healthy NHP was measured by combining fMRI with a normalized functional activation map and general linear modeling.ResultsSTN DBS significantly increased BOLD activation in the sensorimotor cortex, supplementary motor area, caudate nucleus, pedunculopontine nucleus, cingulate, insular cortex, and cerebellum (FDR < 0.001).ConclusionOur results demonstrate that STN DBS evokes neural network grouping within the motor network and the basal ganglia. Taken together, these data highlight the importance and specificity of neural circuitry activation patterns and functional connectivity.     

Elevated Antisaccade Error Rate as an Intermediate Phenotype for Psychosis Across Diagnostic Categories

Background: Elevated antisaccade error rate, reflecting problems with inhibitory behavioral control, is a promising intermediate phenotype for schizophrenia. Here, we consider whether it marks liability across psychotic disorders via common or different neurophysiological mechanisms and whether it represents a neurocognitive risk indicator apart from the generalized cognitive deficit. Methods: Schizophrenia (n = 267), schizoaffective (n = 150), and psychotic bipolar (n = 202) probands, their first-degree relatives (ns = 304, 193, 242, respectively), and healthy controls (n = 244), participating in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium, performed antisaccade and prosaccade tasks and completed a neuropsychological battery. Results: Antisaccade error rate was elevated in proband groups with greatest deficit observed in schizophrenia and was unrelated to symptoms and antipsychotic treatment. Increased error rate was also observed among relatives, even those without history of psychosis or psychosis spectrum personality traits. Relatives’ deficits were similar across proband diagnoses. Error rate was familial and remained elevated in proband and relative groups after accounting for generalized cognitive impairment. Speed of attentional shifting, indexed by prosaccade latency, was similarly influenced in all groups by manipulations that freed vs increasingly engaged attention systems and was inversely associated with antisaccade error rate in all but schizophrenia probands. Conclusions: These findings indicate that elevated antisaccade error rate represents an intermediate phenotype for psychosis across diagnostic categories, and that it tracks risk beyond that attributable to the generalized cognitive deficit. The greater severity of antisaccade impairment in schizophrenia and its independence from attention shifting processes suggest more severe and specific prefrontal inhibitory control deficits in this disorder.Key words: schizophrenia, schizoaffective disorder, bipolar disorder, endophenotype, family study     

Gait-related frequency modulation of beta oscillatory activity in the subthalamic nucleus of parkinsonian patients

BackgroundAbnormal beta band activity in the subthalamic nucleus (STN) is known to be exaggerated in patients with Parkinson’s disease, and the amplitude of such activity has been associated with akinetic rigid symptoms. New devices for deep brain stimulation (DBS) that operate by adapting the stimulation parameters generally rely on the detection of beta activity amplitude modulations in these patients. Movement-related frequency modulation of beta oscillatory activity has been poorly investigated, despite being an attractive variable for extracting information about basal ganglia activity.ObjectiveWe studied the STN oscillatory activity associated with locomotion and proposed a new approach to extract movement related information from beta band activity.MethodsWe recorded bilateral local field potential of the STN in eight parkinsonian patients implanted with DBS electrodes during upright quiet standing and unperturbed walking. Neurophysiological recordings were combined with kinematic measurements and individual molecular brain imaging studies. We then determined the information carried by the STN oscillatory activity about locomotion and we identified task-specific biomarkers.ResultsWe found a gait-related peak frequency modulation of the beta band of STN recordings of parkinsonian patients. This novel biomarker and the associated power modulations were highly informative to detect the walking state (with respect to standing) in each single patient.ConclusionFrequency modulation in the human STN represents a fundamental aspect of information processing of locomotion. Our information-driven approach could significantly enrich the spectrum of Parkinson’s neural markers, with input signals encoding ongoing tasks execution for an appropriate online tuning of DBS delivery.     

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.     

Deep brain stimulation and medication for parkinsonian tremor during secondary tasks.

This study examined the efficacy of subthalamic nucleus (STN), deep brain stimulation (DBS), and medication for resting tremor during performance of secondary tasks. Hand tremor was recorded using accelerometry and electromyography (EMG) from 10 patients with Parkinson's disease (PD) and ten matched control subjects. The PD subjects were examined off treatment, on STN DBS, on medication, and on STN DBS plus medication. In the first experiment, tremor was recorded in a quiet condition and during a cognitive task designed to enhance tremor. In the second experiment, tremor was recorded in a quiet condition and during isometric finger flexion (motor task) with the contralateral limb at 5% of the maximal voluntary contraction (MVC) that was designed to suppress tremor. Results showed that: (1) STN DBS and medication reduced tremor during a cognitive task that exacerbated tremor, (2) STN DBS normalized tremor frequency in both the quiet and cognitive task conditions, whereas tremor amplitude was only normalized in the quiet condition, (3) a secondary motor task reduced tremor in a similar manner to STN DBS. These findings demonstrate that STN DBS still suppresses tremor in the presence of a cognitive task. Furthermore, a secondary motor task of the opposite limb suppresses tremor to levels comparable to STN DBS.     

Rapid response of parkinsonian tremor to STN‐DBS changes: Direct modulation of oscillatory basal ganglia activity?

Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) has proved to be effective for tremor and other cardinal symptoms in Parkinson's disease (PD), the precise mechanisms of action of DBS are still unclear. We analyzed the time course of resting tremor amplitude and frequency during discontinuation and subsequent reinitiation of STN‐DBS in nine PD patients, using a computerized three‐dimensional motion analysis combined with surface electromyography. Following discontinuation of STN‐DBS, resting tremor amplitude rapidly increased, reaching maximum amplitude after 2 min (mean ± 95%CI: 34.3 ± 13.8 mm; P < 0.01), subsequently stabilizing at a medium level. Reinitiation of stimulation after 30 min resulted in rapid, nearly complete suppression of tremor activity within 1 min (1.4 ± 1.3 mm; P < 0.01) and, furthermore, increased tremor frequency within a few seconds in seven of nine patients. These findings support the hypothesis that STN‐DBS acts by direct interference with the neurotransmission of basal ganglia networks involved in tremor. © 2009 Movement Disorder Society     

Sleep parameters associated with long-term outcome following subthalamic deep brain stimulation in Parkinson's disease

IntroductionWe aimed to investigate the effects of changes in sleep architecture on long-term clinical outcome in patients with Parkinson's disease (PD) who underwent deep brain stimulation of subthalamic nuclei (STN DBS).MethodsWe followed up eight PD patients before and three years after STN DBS surgery. In addition to clinical assessments, polysomnography (PSG) followed by multiple sleep latency tests was performed before and after STN DBS, while stimulator was ON and OFF.ResultsSubjective sleep latency was significantly decreased (P = 0.033) and sleep duration was increased (P = 0.041), as measured by Pittsburgh sleep quality index. Latency to REM sleep stage was shortened after surgery with STN DBS ON (P = 0.002). Index of central type of abnormal respiratory events was significantly increased while stimulator was ON (P = 0.034). Total number of major body movements was found to be increased when stimulator was turned OFF (P = 0.012). Among PSG data obtained during STN DBS ON, it was observed that duration of N3 sleep was negatively correlated with UPDRS scores at 1st (P = 0.038) and 3rd (P = 0.045) post-operative years. Among PSG variables during STN DBS OFF, durations of N3 sleep (P = 0.017) and REM sleep (P = 0.041) were negatively correlated with UPDRS scores at post-operative 1st year.ConclusionDisturbances in sleep architecture are associated with higher UPDRS scores and worse prognosis at 1st and 3rd post-operative years. Similar results obtained while stimulator was OFF at the end of 1st year support the presence of microlesion effect after STN DBS, which is probably not long lasting.     

Effects of Repeated Deep Brain Stimulation on Depressive- and Anxiety-Like Behavior in Rats: Comparing Entopeduncular and Subthalamic Nuclei

BackgroundDeep brain stimulation (DBS) of the subthalamic nucleus (STN) or internal globus pallidus (GPi) has been routinely used for the treatment of some movement disorders. However, DBS may be associated with adverse psychiatric effects, such as depression, anxiety and impulsivity.ObjectiveTo compare DBS applied to the entopeduncular nucleus (EPN; the rodent homolog of the GPi) and STN in terms of their effects on depressive- and anxiety-like behavior in rats.MethodsDBS was applied for 21 days (4 h a day) to either the STN or EPN. Rats then underwent behavioral testing on learned helplessness and elevated plus maze tasks before being sacrificed for brain analyses of zif268, BDNF and trkB mRNA as well as BDNF protein levels.ResultsRepeated DBS of the STN, but not of the EPN, led to impaired performance in the learned helplessness task, suggesting that STN-DBS induces or potentiates depressive-like behavior. There was no effect of DBS on elevated plus maze or on open field behavior. Repeated STN-DBS, but not EPN-DBS, led to decreased levels of BDNF and trkB mRNA in hippocampus. Acute stimulation of the STN or EPN resulted in similar changes in zif268 levels in several brain areas, except for the raphe where decreases were seen only after STB-DBS.ConclusionsTogether these results indicate that the effects of STN- and EPN-DBS differ in behavioral and neurochemical respects. Results further suggest that the EPN may be a preferable target for clinical DBS when psychiatric side effects are considered insofar as it may be associated with a lower incidence of depressive-like behavior than the STN.     

Long-term effects of bilateral deep brain stimulation of the subthalamic nucleus on depression in patients with Parkinson's disease

ObjectiveTo study the long-term effects of deep brain stimulation (DBS) of the bilateral subthalamic nucleus (STN) on depression in patients with Parkinson's disease (PD) and to discuss the mechanism.MethodsA STN–DBS group (n = 27) and anti-Parkinson's medication control group with paired designing were set up. The evaluation of the depression and motor function was performed a total of six times. Depression was evaluated by the Self-Rating Depression Scale (SDS) and Hamilton Rating Scale for Depression (HAMD). Motor function was evaluated by the third part of the Unified Parkinson's Disease Rating Scale (UPDRS-III).ResultsCompared with the preoperative and the medication control group, the UPDRS-III scores of the STN–DBS group decreased remarkably within 18 months postoperatively (P ≤ 0.001), and the SDS scores decreased notably within 6 months postoperatively (P ≤ 0.05), and the HAMD scores decreased notably within 3 months postoperatively (P ≤ 0.05). The UPDRS-III scores were strongly correlated with their SDS scores within 6 months postoperatively (P ≤ 0.05), especially at 5 weeks postoperation (P ≤ 0.001). UPDRS-III scores were also strongly correlated with HAMD scores at 5 weeks postoperation (P ≤ 0.05). The mean value of the bilateral voltages was obviously correlated with SDS and HAMD scores (P ≤ 0.05) within 18 months postoperatively.ConclusionThe improvement in motor symptoms resulting from STN–DBS can improve depression in PD patients, but its long-term effects were unremarkable. Within the treatment range, the higher the mean value of bilateral voltages then the more severe was the depression in PD patients.     

fMRI of Deep Brain Stimulation at the Rat Ventral Posteromedial Thalamus

BackgroundFunctional magnetic resonance imaging (fMRI) of deep brain stimulation (DBS) has potentials to reveal neuroanatomical connectivity of a specific brain region in vivo.ObjectiveThis study aimed to demonstrate frequency and amplitude tunings of the thalamocortical tract using DBS fMRI at the rat ventral posteromedial thalamus.MethodsBlood oxygenation level dependent (BOLD) fMRI data were acquired in a total of twelve rats at a high-field 11.7 T MRI scanner with modulation of nine stimulus frequencies (1–40 Hz) and seven stimulus amplitudes (0.2–3.6 mA).ResultsBOLD response in the barrel cortex peaked at 25 Hz. The response increased with stimulus amplitude and reached a plateau at 1 mA. Cortical spreading depolarization (CSD) was observed occasionally after DBS that carries >10% BOLD waves spanning the entire ipsilateral cortex.ConclusionfMRI is sensitive to the frequency effect of DBS and has potential to investigate the function of a particular neuroanatomical pathway.     

Lexical-semantic inhibitory mechanisms in Parkinson's disease as a function of subthalamic stimulation

Inhibitory control may be affected by Parkinson's disease (PD) due to impairment within the non-motor basal ganglia-thalamocortical circuits. The present study aimed to identify the effects of chronic stimulation of the subthalamic nucleus (STN) on lexical-semantic inhibitory control. Eighteen participants with PD who had undergone surgery for deep brain stimulation (DBS) of the STN, completed a picture-word interference (PWI) task and the Hayling test in on and off stimulation conditions. The results of PD participants were compared with 21 non-neurologically impaired control participants. PD participants performed no differently from controls on the PWI task, and no significant differences between on and off stimulation conditions were revealed, therefore suggesting that PD participants are not impaired in lexical-semantic interference control. In contrast, in the off stimulation condition, PD participants had significantly delayed reaction times and increased errors on the inhibition section of the Hayling test compared with the STN stimulation condition and control participants. These results suggest that PD patients are impaired in aspects of inhibitory control that are dependent on behavioural inhibition (such as the suppression of prepotent responses) and selection from competing alternatives without the presence of external cues. Furthermore, STN stimulation acts to restore these behavioural inhibitory processes.     

Cognitive effects of theta frequency bilateral subthalamic nucleus stimulation in Parkinson’s disease: A pilot study

BackgroundThere is significant evidence for cognitive decline following deep brain stimulation (DBS). Current stimulation paradigms utilize gamma frequency stimulation for optimal motor benefits; however, little has been done to optimize stimulation parameters for cognition. Recent evidence implicates subthalamic nucleus (STN) theta oscillations in executive function, and theta oscillations are well-known to relate to episodic memory, suggesting that theta frequency stimulation could potentially improve cognition in Parkinson’s disease (PD).ObjectiveTo evaluate the acute effects of theta frequency bilateral STN stimulation on executive function in PD versus gamma frequency and off, as well as investigate the differential effects on episodic versus nonepisodic verbal fluency.MethodsTwelve patients (all males, mean age 60.8) with bilateral STN DBS for PD underwent a double-blinded, randomized cognitive testing during stimulation at (1) 130–135 Hz (gamma), (2) 10 Hz (theta) and (3) off. Executive functions and processing speed were evaluated using verbal fluency tasks (letter, episodic category, nonepisodic category, and category switching), color-word interference task, and random number generation task. Performance at each stimulation frequency was compared within subjects.ResultsTheta frequency significantly improved episodic category fluency compared to gamma, but not compared to off. There were no significant differences between stimulation frequencies in other tests.ConclusionIn this pilot trial, our results corroborate the role of theta oscillations in episodic retrieval, although it is unclear whether this reflects direct modulation of the medial temporal lobe and whether similar effects can be found with more canonical memory paradigms. Further work is necessary to corroborate our findings and investigate the possibility of interleaving theta and gamma frequency stimulation for concomitant motor and cognitive effects.     

Effect of subthalamic deep brain stimulation on turning kinematics and related saccadic eye movements in Parkinson disease

BackgroundPersons with Parkinson disease (PD) experience turning difficulty, often leading to freezing of gait and falls. Visual information plays a significant role in locomotion and turning, and while the effects of deep brain stimulation (DBS) on oculomotor function have been well documented, the effects of DBS on oculomotor function during turning and on turning itself have yet to be fully elucidated.ObjectiveTo determine the effects of STN DBS on turning performance and related oculomotor performance in PD.MethodsEleven subjects with PD and DBS of the subthalamic nucleus performed a seated voluntary saccade task and standing 180° turns in DBS OFF and DBS ON conditions. Oculomotor data were captured using an infrared eye tracking system while segment rotations were measured using 3-D motion capture.ResultsDuring the seated saccade task, DBS did not improve saccade amplitude or latency. DBS also did not improve gait velocity and stride length during forward walking. During turning, DBS improved turn performance (turn duration), reduced the number of saccades performed during the turns, and increased the amplitude and velocity of the saccade initiating the turn. DBS decreased the intersegmental latencies (eye–head, eye–foot, and head–trunk) but this effect was lost for eye–head and eye–foot after controlling for the duration of the first gait cycle.ConclusionsDBS significantly improves turn performance and related oculomotor performance. These findings add to the growing list of therapeutic benefits offered by DBS.