Movement-related changes in local and long-range synchronization in Parkinson's disease revealed by simultaneous magnetoencephalography and intracranial recordings

Functional neurosurgery has afforded the opportunity to assess interactions between populations of neurons in the human cerebral cortex and basal ganglia in patients with Parkinson's disease (PD). Interactions occur over a wide range of frequencies, and the functional significance of those >30 Hz is particularly unclear. Do they improve movement, and, if so, in what way? We acquired simultaneously magnetoencephalography and direct recordings from the subthalamic nucleus (STN) in 17 PD patients. We examined the effect of synchronous and sequential finger movements and of the dopamine prodrug levodopa on induced power in the contralateral primary motor cortex (M1) and STN and on the coherence between the two structures. We observed discrete peaks in M1 and STN power at 60-90 Hz and at 300-400 Hz. All these power peaks increased with movement and levodopa treatment. Only STN activity at 60-90 Hz was coherent with activity in M1. Directionality analysis showed that STN gamma activity at 60-90 Hz tended to drive gamma activity in M1. The effects of levodopa on both local and distant synchronization at 60-90 Hz correlated with the degree of improvement in bradykinesia-rigidity as did local STN activity at 300-400 Hz. Despite this, there were no effects of movement type, nor interactions between movement type and levodopa in the STN, nor in the coherence between STN and M1. We conclude that synchronization at 60-90 Hz in the basal ganglia cortical network is prokinetic but likely through a modulatory effect rather than any involvement in explicit motor processing.     

Deep brain stimulation of the pedunculopontine tegmental nucleus modulates neuronal hyperactivity and enhanced beta oscillatory activity of the subthalamic nucleus in the rat 6-hydroxydopamine model

Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) area has been introduced as a novel surgical therapy for dopamine refractory gait problems, freezing and postural instability in the late stage of Parkinson's disease (PD). Lesions of the pedunculopontine tegmental (PPTg) nucleus, the equivalent of the PPN in rodents, were shown to reduce the elevated discharge rate of the subthalamic nucleus (STN) in the 6-hydroxydopamine (6-OHDA) rat model of PD. In order to further elucidate the modulatory effect of the PPTg on the STN we examined the effect of 25 Hz low frequency PPTg stimulation on neuronal single unit activity and oscillatory local field potentials (LFPs) of the STN, and on the electrocorticogram (ECoG) of the primary motor cortex region in rats with unilateral 6-OHDA induced nigrostriatal lesions. Stimulation of the PPTg reduced the enhanced firing rate in the STN, without affecting the firing pattern or approximate entropy (ApEn). It also reduced the activity in the beta band (15-30 Hz) of the STN, which is elevated in 6-OHDA lesioned rats, without affecting beta activity in the motor cortex. We showed a modulatory effect of PPTg stimulation on altered neuronal STN activity in the PD 6-OHDA rat model, indicating that PPTg DBS may alter activity of the basal ganglia circuitry at least partially. It remains unclear, however, how these changes are exactly mediated and whether they are relevant with regard to the descending PPTg projections in the lower brainstem.     

Bilateral symmetry and coherence of subthalamic nuclei beta band activity in Parkinson's disease

Abnormal synchronization of neuronal activity in the basal ganglia has been associated with the dysfunction of sensorimotor circuits in Parkinson's disease (PD). In particular, oscillations at frequencies within the beta range (13-35 Hz) are specifically modulated by dopaminergic medication and are correlated with the clinical state of the subjects. While these oscillations have been shown to be coherent ipsilaterally within the basal ganglia and between the basal ganglia nuclei and the ipsilateral motor cortex in PD, the bilateral extent of their coherence has never been characterized. Here we demonstrate for the first time that the beta band oscillations recorded in the local field potential of the subthalamic nuclei (STN), while appearing different across subjects, are occurring at the same frequencies bilaterally (p < 0.001) and are coherent between the two STNs of individual PD subjects (11/12 cases, p < 0.05). These findings suggest the existence of a bilateral network controlling the beta band activity in the basal ganglia in PD.     

High‐frequency stimulation of the subthalamic nucleus restores neural and behavioral functions during reaction time task in a rat model of Parkinson's disease

Deep brain stimulation (DBS) has been used in the clinic to treat Parkinson's disease (PD) and other neuropsychiatric disorders. Our previous work has shown that DBS in the subthalamic nucleus (STN) can improve major motor deficits, and induce a variety of neural responses in rats with unilateral dopamine (DA) lesions. In the present study, we examined the effect of STN DBS on reaction time (RT) performance and parallel changes in neural activity in the cortico‐basal ganglia regions of partially bilateral DA‐ lesioned rats. We recorded neural activity with a multiple‐channel single‐unit electrode system in the primary motor cortex (MI), the STN, and the substantia nigra pars reticulata (SNr) during RT test. RT performance was severely impaired following bilateral injection of 6‐OHDA into the dorsolateral part of the striatum. In parallel with such behavioral impairments, the number of responsive neurons to different behavioral events was remarkably decreased after DA lesion. Bilateral STN DBS improved RT performance in 6‐OHDA lesioned rats, and restored operational behavior‐related neural responses in cortico‐basal ganglia regions. These behavioral and electrophysiological effects of DBS lasted nearly an hour after DBS termination. These results demonstrate that a partial DA lesion‐induced impairment of RT performance is associated with changes in neural activity in the cortico‐basal ganglia circuit. Furthermore, STN DBS can reverse changes in behavior and neural activity caused by partial DA depletion. The observed long‐lasting beneficial effect of STN DBS suggests the involvement of the mechanism of neural plasticity in modulating cortico‐basal ganglia circuits. © 2009 Wiley‐Liss, Inc.     

Dopamine lesion-induced changes in subthalamic nucleus activity are not associated with alterations in firing rate or pattern in layer V neurons of the anterior cingulate cortex in anesthetized rats

Dysfunctional activity in the subthalamic nucleus (STN) is thought to underlie movement deficits of patients with Parkinson's disease. Alterations in STN firing patterns are also evident in the anesthetized rat model of Parkinson's disease, where studies show that loss of striatal dopamine and concomitant changes in the indirect pathway are associated with bursty and oscillatory firing patterns in STN output. However, the extent to which alterations in cortical activity contribute to changes in STN activity is unclear. As pyramidal neurons in the cingulate cortex project directly to the STN, cingulate output was assessed after dopamine lesion by simultaneously recording single-unit and local field potential (LFP) activities in STN and anterior cingulate cortex in control, dopamine-lesioned and non-lesioned hemispheres of urethane-anesthetized rats. Correlated oscillations were observed in cross-correlograms of spike trains from STN and cingulate layer V neurons with broad waveforms indicative of pyramidal neurons. One-2 weeks after dopamine cell lesion, firing rate, incidence of bursty and 0.3-2.5 Hz oscillatory activity of neurons and LFP power in the STN all increased significantly. In contrast, firing rate, incidence of bursty and 0.3-2.5 Hz oscillatory activity of cingulate layer V putative pyramidal neurons and power in cingulate LFPs did not differ significantly between dopamine-lesioned, non-lesioned or control hemispheres, despite significant loss of dopamine in the lesioned cingulate cortex. Data show that alterations in STN activity in the dopamine-lesioned hemisphere are not associated with alterations in neuronal activity in layer V of the anterior cingulate cortex in anesthetized rats.     

Levodopa-induced modulation of subthalamic beta oscillations during self-paced movements in patients with Parkinson's disease

Excessive synchronization of neural activity in the beta frequency band ( approximately 20 Hz) within basal ganglia circuits might contribute to the paucity and slowness of movement in Parkinson's disease (PD). Treatment with dopaminergic drugs reduces the background level of beta frequency band synchronization in the subthalamic nucleus (STN), but has not been shown to increase the proportion of beta activity that is suppressed before voluntary movement in PD. We assessed changes in the event-related desynchronization (ERD) in the beta frequency band of local field potential signals from the region of the STN in 14 patients with PD as they performed self-paced movements of a joystick before and after levodopa administration. The dopamine precursor, levodopa, increased the duration and magnitude of the premovement beta ERD, but did not alter postmovement synchronization in the beta band. Both the latency and magnitude of the beta ERD inversely correlated with the degree of motor impairment. These findings suggest that the beta ERD recorded in the STN area reflects motor-preparative processes that are at least partly dependent on dopaminergic activity within the basal ganglia.     

The STN beta-band profile in Parkinson's disease is stationary and shows prolonged attenuation after deep brain stimulation

Producing accurate movements may rely on the functional independence of sensorimotor circuits within basal ganglia nuclei. In parkinsonism there is abnormal synchrony of electrical activity within these circuits that results in a loss of independence across motor channels. Local field potential (LFP) recordings reflect the summation of local electrical fields and an increase in LFP power reflects increased synchrony in local neuronal networks. We recorded LFPs from the subthalamic nucleus (STN) deep brain stimulation (DBS) lead in the operating room in 22 cases from 16 subjects with Parkinson's disease (PD) who were off medication. There was elevated LFP power at beta frequencies (13-35 Hz) at rest. The LFP spectral profile was consistent across several periods of rest that were separated by movement and/or DBS, and appeared to be a relatively stationary phenomenon. The spectral profile and frequencies of the beta-band peak(s) varied among subjects but were similar between the right and left STNs within certain individuals. These results suggest that the LFP spectrum at rest may characterize a “signature” rhythm for an individual with PD. Beta-band power was attenuated after intra-operative STN DBS (p < 0.05). The attenuation lasted for 10 s after short periods (30 s) and for up to 50 s after longer periods (5 min) of DBS. The finding that longer periods of DBS attenuated beta power for a longer time suggests that there may be long-acting functional changes to networks in the STN in PD after chronic DBS.     

Characterisation of tremor-associated local field potentials in the subthalamic nucleus in Parkinson's disease

We simultaneously recorded local field potentials (LFPs) in the subthalamic nucleus (STN) and surface electromyographic signals (EMGs) from the extensor and flexor muscles of the contralateral forearm in eight patients with idiopathic tremor-dominant Parkinson's disease (resting tremor) during the bilateral implantation of deep brain stimulation electrodes. Recordings were made at different heights (in 0.5- to 2.0-mm steps beginning outside the STN) using up to five concentrically configured macroelectrodes (2 mm apart). The patients were instructed to relax their contralateral forearm (rest condition). We analysed the coherence between tremor EMGs and STN LFPs, which showed significant tremor-associated coupling at single tremor and double tremor frequencies. Moreover, the EMG–LFP coherences were characterised by differences between antagonistic muscles (flexor, extensor) and by the spatial distribution of LFPs within the STN. Coherence at single and double tremor frequencies occurred significantly more frequently within STN than above STN (in the zona incerta). In this study, we were able to show that, within STN, tremor-associated LFP activity varied with spatial distribution and with the contralateral antagonistic forearm muscles. These findings suggest the existence of distribution- and muscle-specific tremor-associated LFP activity at different tremor frequencies and an organisation of tremor-related subloops within the STN.     

Directional communication during movement execution interferes with tremor in Parkinson's disease

Background : Both the cerebello‐thalamo‐cortical circuit and the basal ganglia/cortical motor loop have been postulated to be generators of tremor in PD. The recent suggestion that the basal ganglia trigger tremor episodes and the cerebello‐thalamo‐cortical circuitry modulates tremor amplitude combines both competing hypotheses. However, the role of the STN in tremor generation and the impact of proprioceptive feedback on tremor suppression during voluntary movements have not been considered in this model yet. Objectives : The objective of this study was to evaluate the role of the STN and proprioceptive feedback in PD tremor generation during movement execution. Methods: Local‐field potentials of the STN as well as electromyographical and electroencephalographical rhythms were recorded in tremor‐dominant and nontremor PD patients while performing voluntary movements of the contralateral hand during DBS surgery. Effective connectivity between these electrophysiological signals were analyzed and compared to electromyographical tremor activity. Results: There was an intensified information flow between the STN and the muscle in the tremor frequencies (5‐8 Hz) for tremor‐dominant, in comparison to nontremor, patients. In both subtypes, active movement was associated with an increase of afferent interaction between the muscle and the cortex in the β‐ and γ‐frequencies. The γ‐frequency (30‐40 Hz) of this communication between muscle and cortex correlated inversely with electromyographical tremor activity. Conclusions : Our results indicate an involvement of the STN in propagation of tremor‐related activity to the muscle. Furthermore, we provide evidence that increased proprioceptive information flow during voluntary movement interferes with central tremor generation. © 2018 International Parkinson and Movement Disorder Society     

Parafascicular thalamic nucleus activity in a rat model of Parkinson's disease

Parkinson's disease is associated with increased oscillatory firing patterns in basal ganglia output, which are thought to disrupt thalamocortical activity. However, it is unclear how specific thalamic nuclei are affected by these changes in basal ganglia activity. The thalamic parafascicular nucleus (PFN) receives input from basal ganglia output nuclei and directly projects to the subthalamic nucleus (STN), striatum and cortex; thus basal ganglia-mediated changes on PFN activity may further impact basal ganglia and cortical functions. To investigate the impact of increased oscillatory activity in basal ganglia output on PFN activity after dopamine cell lesion, PFN single-unit and local field potential activities were recorded in neurologically intact (control) rats and in both non-lesioned and dopamine lesioned hemispheres of unilateral 6-hydroxydopamine lesioned rats anesthetized with urethane. Firing rates were unchanged 1–2 weeks after lesion; however, significantly fewer spontaneously active PFN neurons were evident. Firing pattern assessments after lesion showed that a larger proportion of PFN spike trains had 0.3–2.5 Hz oscillatory activity and significantly fewer spike trains exhibited low threshold calcium spike (LTS) bursts. In paired recordings, more PFN–STN spike oscillations were significantly correlated, but as these oscillations were in-phase, results are inconsistent with feedforward control of PFN activity by inhibitory oscillatory basal ganglia output. Furthermore, the decreased incidence of LTS bursts is incompatible with inhibitory basal ganglia output inducing rebound bursting in PFN after dopamine lesion. Together, results show that robust oscillatory activity observed in basal ganglia output nuclei after dopamine cell lesion does not directly drive changes in PFN oscillatory activity.     

Interhemispheric functional interactions between the subthalamic nuclei of patients with Parkinson's disease

Parkinson's disease (PD) is characterized by widespread neural interactions in cortico‐basal‐ganglia networks primarily in beta oscillations (approx. 10–30 Hz), as suggested by previous findings of levodopa‐modulated interhemispheric coherence between the bilateral subthalamic nuclei (STN) in local field potential recordings (LFPs). However, due to confounding effects of volume conduction the existence of ‘genuine’ interhemispheric subcortical coherence remains an open question. To address this issue we utilized the imaginary part of coherency (iCOH) which, in contrast to the standard coherence, is not susceptible to volume conduction. LFPs were recorded from eight patients with PD during wakeful rest before and after levodopa administration. We demonstrated genuine coherence between the bilateral STN in both 10–20 and 21–30 Hz oscillations, as revealed by a non‐zero iCOH. Crucially, increased iCOH in 10–20 Hz oscillations positively correlated with the worsening of motor symptoms in the OFF medication condition across patients, which was not the case for standard coherence. Furthermore, across patients iCOH was increased after levodopa administration in 21–30 Hz oscillations. These results suggest a functional distinction between low and high beta oscillations in STN‐LFP in line with previous studies. Furthermore, the observed functional coupling between the bilateral STN might contribute to the understanding of bilateral effects of unilateral deep brain stimulation. In conclusion, the present results imply a significant contribution of time‐delayed neural interactions to interhemispheric coherence, and the clinical relevance of long‐distance neural interactions between bilateral STN for motor symptoms in PD.     

Subthalamic nucleus stimulation and lesioning have distinct state‐dependent effects upon striatal dopamine metabolism

The mechanism by which deep brain stimulation (DBS) of the subthalamic nucleus (STN) achieves its effects in Parkinson's disease (PD) is not known. In animal models of PD, stimulation and lesioning of the STN have some effects which are the same, but others which differ, in reversing cellular and behavioral changes induced by dopamine depletion. We compared the effects of short‐term STN stimulation and lesions upon extracellular levels of dopamine and metabolites using in vivo microdialysis of the dorsal striatum of awake, intact and unilateral 6‐hydroxydopamine (6OHDA)‐lesioned rats. STN stimulation in control rats decreased striatal dopamine levels and caused a relative increase in dopamine metabolism, as expressed by HVA/dopamine and DOPAC/dopamine ratios. This suggests an increase in both vesicular dopamine release (metabolized to HVA), and release from the cytoplasmic dopamine pool (metabolized to DOPAC). STN lesions in control rats increased the HVA/dopamine ratio, also suggesting a relative increase in vesicular dopamine release. These results indicate that STN stimulation and lesioning can affect striatal dopamine metabolism in the intact system. In 6OHDA‐lesioned rats at baseline, metabolic ratios were markedly decreased as compared with controls. STN lesions of 6OHDA‐lesioned rats did not affect relative metabolic ratios as compared with baseline levels. In 6‐OHDA‐lesioned rats, STN stimulation decreased extracellular levels of dopamine, and, to a greater extent, metabolites, resulting in a decrease in metabolic ratios. This further decrease in dopamine turnover with STN stimulation would serve to maintain dopamine levels in the dopamine‐depleted striatum, and may account for the therapeutic benefit of DBS in Parkinson's disease. Synapse 63:136–146, 2009. Published 2008 Wiley‐Liss, Inc.     

Pathophysiological mechanisms implicated by high-frequency stimulation in Parkinson's disease: the restoration of high and low frequency oscillatory systems

INTRODUCTION: Increased neuronal activity in the internal pallidum (GPi) and the subthalamic nucleus (STN) has been clearly demonstrated in Parkinsonian models, and the two structures have thus been selected as therapeutic targets for functional neurosurgery. High-frequency electrical stimulation of the GPi or the STN improves the parkinsonian symptoms but also dyskinesias directly by GPi stimulation or indirectly by reduction of L-Dopa associated with STN stimulation. According to Alexander's model of the organisation of the basal ganglia, electrical stimulation of GPi or STN should have led to uncontrolled hyperkinesia. This apparent paradox could be explained on one hand by the involvement of different anatomo-functional areas within these structures and on the other by spatial and temporal changes in neuronal discharge patterns in the basal ganglia which in turn produce variations in synchronisation. RESULTS: Event-related (de)synchronisation (ERD) has enabled us to study variations in subcortico-cortical oscillatory activity: it has been shown that high-frequency electrical stimulation of the GPi/STN increases desynchronisation of low frequency rhythms (mu and beta,<30 Hz) during movement preparation and execution and augments post-movement synchronisation. Stimulation also decreases the abnormal frontocentral spreading of desynchronisation during movement preparation. CONCLUSIONS: In accordance with previous coherence analyses, electrical stimulation of STN is likely to restore the activity of high-frequency and low-frequency systems, as evidenced by a decrease in the hypersynchronisation of low-frequency rhythms at rest and restoral of a high-frequency rhythm during movement. Stimulation may improve spatial selectivity by activating the selected programs in conjunction with the primary sensorimotor cortex, whilst inhibiting competitive programs represented by abnormal spreading outside the primary sensorimotor cortex.     

Facing the lack of anti-phase oscillation in the parafascicular nucleus after dopamine depletion

There is a large body of literature establishing that excessive neuronal synchronization and a shift in firing pattern within the cortico-basal ganglia circuit is implicated in Parkinson's disease (PD), yet a causal link between abnormal network oscillation and specific deficits in PD is lacking. It is proposed that enhanced (inhibitory) synchronous basal ganglia output could trigger anti-phase oscillatory activity in target thalamic nuclei, and entrain this abnormal synchronization within the cortico-basal ganglia loop through a reciprocal resonance mechanism. In a recent Experimental Neurology paper (2009), Parr-Brownlie et al. addressed this issue by assessing electrophysiological recordings in vivo in anesthetized control and dopamine-depleted rats induced by unilateral injection of 6-hydroxydopamine. Results from this study demonstrate that a shift in firing pattern in basal ganglia output neurons does not directly drive the distinctive oscillatory activity observed in the parafascicular nucleus after dopamine depletion. This commentary discusses possible mechanisms mediating the altered oscillatory activity found in the parafascicular nucleus after dopamine depletion and its link to the increased in-phase oscillations with synchronous firing in the subthalamic nucleus.     

High frequency stimulation of the subthalamic nucleus increases the extracellular contents of striatal dopamine in normal and partially dopaminergic denervated rats

The subthalamic nucleus (STN) has come under focus in Parkinson disease (PD) because of recent advances in the understanding of the functional organization of the basal ganglia in normal and pathological conditions. Manipulations of the STN have been described to compensate for some imbalance in motor output of the basal ganglia in animal models of PD and have been proposed as a potential therapeutic target in humans. Indeed, high frequency stimulation (HFS) (130 Hz) of the STN has beneficial effects in severe parkinsonian patients but the precise mechanisms underlying these clinical results remain to be elucidated. To date, very little is known concerning the effect of HFS-STN on striatal dopaminergic transmission. Since it has been reported that dopaminergic medication may be reduced in PD patients under HFS-STN, our goal was to study the effect of HFS-STN on striatal dopamine (DA) transmission by using intracerebral microdialysis in normal and partially DA denervated rats. Our results show that HFS STN induces a significant increase of extracellular DA in the striatum of normal and partially DA lesioned rats while striatal extracellular levels of DOPAC were not affected. We conclude that HFS-STN acts directly and/or indirectly on striatal DA levels in control or partially DA lesioned rats.     

Subthalamic gamma activity in patients with Parkinson's disease

Depth recordings in patients with Parkinson's disease (PD) have demonstrated oscillatory activity in the gamma frequency (60-100 Hz) band in local field potentials (LFPs) recorded from the region of the subthalamic nucleus (STN). Although this activity has been hypothesised to contribute to movement preparation, it is unclear to what extent these LFP oscillations arise in the STN and are synchronous with local neuronal discharge. We therefore recorded LFPs and neuronal activity from microelectrodes inserted into the STN in PD patients during functional neurosurgery. Eight sides in seven patients out of 15 sides in 12 patients were identified that had peaks in the gamma band in spectra of LFPs. As microelectrodes descended towards STN, there was a pronounced increase in gamma frequency band LFP activity 1 mm above the line joining the anterior and posterior commissures and 2 mm above the microelectrode defined dorsal border of the STN. Gamma activity dropped again 3 mm below the microelectrode defined dorsal border of the STN. Spike-triggered averages of LFP activity suggested that the discharges of neurons in this region were locked to gamma oscillations in the LFP. Gamma band oscillations in the LFP are therefore likely to represent synchronous activity in populations of neurons in the upper STN and bordering zona incerta of patients with PD.     

Neuronal activity in the medial associative‐limbic and lateral motor part of the rat subthalamic nucleus and the effect of 6‐hydroxydopamine‐induced lesions of the dorsolateral striatum

Lesions of the rat nigrostriatal dopamine system by injection of 6‐hydroxydopamine (6‐OHDA) lead to abnormal neuronal activity in the basal ganglia (BG) motor loop similar to that found in Parkinson's disease (PD). In the BG motor loop the subthalamic nucleus (STN) represents an important structure, which, however, also comprises areas of the BG associative and limbic loops. We were interested whether neuronal activity would differ between the STN medial associative‐limbic and lateral motor part, and whether selective 6‐OHDA‐induced lesions of the dorsolateral striatum, the entrance region of the BG motor loop, would differently affect these subregions. In male Sprague–Dawley rats 6‐OHDA (n = 12) or vehicle (n = 10) was bilaterally injected in the dorsolateral striatum. Four weeks later extracellular single‐unit activity and local field potentials were recorded in medial and lateral STN neurons of urethane‐anesthetized rats. In sham‐lesioned rats the discharge rate and burst activity were higher in the lateral compared to the medial STN. Similar differences were found for other neuronal activity measures (coefficient of variation of interspike interval, skewness, kurtosis, approximate entropy). After 6‐OHDA injection neuronal burst activity was enhanced, while the discharge rate was not affected. In addition, in 6‐OHDA‐lesioned rats β‐band oscillatory activity was enhanced, with no difference between STN subregions. We found important differences of neuronal activity between STN subregions, indicating functional segregation. However, selective 6‐OHDA lesions of the dorsolateral striatum also had a pronounced effect on the medial STN subregion, indicating interaction between BG loops. J. Comp. Neurol. 521:3226–3240, 2013. © 2013 Wiley Periodicals, Inc.     

Input Zone-Selective Dysrhythmia in Motor Thalamus after Dopamine Depletion

The cerebral cortex, basal ganglia and motor thalamus form circuits important for purposeful movement. In Parkinsonism, basal ganglia neurons often exhibit dysrhythmic activity during, and with respect to, the slow (∼1 Hz) and beta-band (15-30 Hz) oscillations that emerge in cortex in a brain state-dependent manner. There remains, however, a pressing need to elucidate the extent to which motor thalamus activity becomes similarly dysrhythmic after dopamine depletion relevant to Parkinsonism. To address this, we recorded single-neuron and ensemble outputs in the basal ganglia-recipient zone (BZ) and cerebellar-recipient zone (CZ) of motor thalamus in anesthetized male dopamine-intact rats and 6-OHDA-lesioned rats during two brain states, respectively defined by cortical slow-wave activity and activation. Two forms of thalamic input zone-selective dysrhythmia manifested after dopamine depletion: (1) BZ neurons, but not CZ neurons, exhibited abnormal phase-shifted firing with respect to cortical slow oscillations prevalent during slow-wave activity; and (2) BZ neurons, but not CZ neurons, inappropriately synchronized their firing and engaged with the exaggerated cortical beta oscillations arising in activated states. These dysrhythmias were not accompanied by the thalamic hypoactivity predicted by canonical firing rate-based models of circuit organization in Parkinsonism. Complementary recordings of neurons in substantia nigra pars reticulata suggested that their altered activity dynamics could underpin the BZ dysrhythmias. Finally, pharmacological perturbations demonstrated that ongoing activity in the motor thalamus bolsters exaggerated beta oscillations in motor cortex. We conclude that BZ neurons are selectively primed to mediate the detrimental influences of abnormal slow and beta-band rhythms on circuit information processing in Parkinsonism.SIGNIFICANCE STATEMENT Motor thalamus neurons mediate the influences of basal ganglia and cerebellum on the cerebral cortex to govern movement. Chronic depletion of dopamine from the basal ganglia causes some symptoms of Parkinson''s disease. Here, we elucidate how dopamine depletion alters the ways motor thalamus neurons engage with two distinct oscillations emerging in cortico-basal ganglia circuits in vivo. We discovered that, after dopamine depletion, neurons in the thalamic zone receiving basal ganglia inputs are particularly prone to becoming dysrhythmic, changing the phases and/or synchronization (but not rate) of their action potential firing. This bolsters cortical dysrhythmia. Our results provide important new insights into how aberrant rhythmicity in select parts of motor thalamus could detrimentally affect neural circuit dynamics and behavior in Parkinsonism.     

Intra-operative STN DBS attenuates the prominent beta rhythm in the STN in Parkinson's disease

Power spectra from local field potentials (LFPs) recorded post-operatively from the deep brain stimulation (DBS) macroelectrode show prominence of the beta rhythm (11-30 Hz) in untreated Parkinson's disease (PD). Dopaminergic medication and movement attenuate this beta band in PD. In this pilot study of six sides in four patients, we recorded LFPs from the DBS electrode in untreated PD patients in the operating room. In all cases, there was a peak in the time-frequency spectrogram in the beta frequency range when the patients were at rest, which was associated with attenuation in the same range with movement. The actual frequency range and the strength of the beta peak varied among cases. In two patients, intra-operative constraints permitted recording of LFPs at rest, before and immediately after subthalamic nucleus (STN) DBS. In both patients we documented that STN DBS caused a significant attenuation in power in the beta band at rest that persisted for 15-25 s after DBS had been turned off (P < 0.01). From one case, our data suggest that the beta rhythm attenuation was most prominent within the STN itself. This study shows for the first time that STN DBS attenuates the power in the prominent beta band recorded in the STN of patients with PD. These pilot findings raise the interesting possibility of using this biomarker for closed loop DBS or neuromodulation.     

Subthalamic nucleus stimulation restores glucose metabolism in associative and limbic cortices and in cerebellum: evidence from a FDG-PET study in advanced Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a highly effective surgical treatment in patients with advanced Parkinson's disease (PD). Because the STN has been shown to represent an important relay station not only in motor basal ganglia circuits, the modification of brain areas also involved in non-motor functioning can be expected by this intervention. To determine the impact of STN-DBS upon the regional cerebral metabolic rate of glucose (rCMRGlc), we performed positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) in eight patients with advanced PD before surgery as well as in the DBS on- and off-conditions 4 months after electrode implantation and in ten age-matched healthy controls. Before surgery, PD patients showed widespread bilateral reductions of cortical rCMRGlc versus controls but a hypermetabolic state in the left rostral cerebellum. In the STN-DBS on-condition, clusters of significantly increased rCMRGlc were found in both lower thalami reaching down to the midbrain area and remote from the stimulation site in the right frontal cortex, temporal cortex, and parietal cortex, whereas rCMRGlc significantly decreased in the left rostral cerebellum. Therefore, STN-DBS was found to suppress cerebellar hypermetabolism and to partly restore physiologic glucose consumption in limbic and associative projection territories of the basal ganglia. These data suggest an activating effect of DBS upon its target structures and confirm a central role of the STN in motor as well as associative, limbic, and cerebellar basal ganglia circuits.