Alek Pogosyan

High-frequency stimulation of the subthalamic nucleus suppresses oscillatory beta activity in patients with Parkinson's disease in parallel with improvement in motor performance.

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is a well-established therapy for patients with severe Parkinsons disease (PD), but its mechanism of action is unclear. Exaggerated oscillatory synchronization in the β (13–30 Hz) frequency band has been associated with bradykinesia in patients with PD. Accordingly, we tested the hypothesis that the clinical benefit exerted by STN HFS is accompanied by suppression of local β activity. To this end, we explored the after effects of STN HFS on the oscillatory local field potential (LFP) activity recorded from the STN immediately after the cessation of HFS in 11 PD patients. Only patients that demonstrated a temporary persistence of clinical benefit after cessation of HFS were analyzed. STN HFS led to a significant reduction in STN LFP β activity for 12 s after the end of stimulation and a decrease in motor cortical–STN coherence in the β band over the same time period. The reduction in LFP β activity correlated with the movement amplitude during a simple motor task, so that a smaller amount of β activity was associated with better task performance. These features were absent when power in the 5–12 Hz frequency band was considered. Our findings suggest that HFS may act by modulating pathological patterns of synchronized oscillations, specifically by reduction of pathological β activity in PD.

Disrupted Dopamine Transmission and the Emergence of Exaggerated Beta Oscillations in Subthalamic Nucleus and Cerebral Cortex

In the subthalamic nucleus (STN) of Parkinsons disease (PD) patients, a pronounced synchronization of oscillatory activity at beta frequencies (15–30 Hz) accompanies movement difficulties. Abnormal beta oscillations and motor symptoms are concomitantly and acutely suppressed by dopaminergic therapies, suggesting that these inappropriate rhythms might also emerge acutely from disrupted dopamine transmission. The neural basis of these abnormal beta oscillations is unclear, and how they might compromise information processing, or how they arise, is unknown. Using a 6-hydroxydopamine-lesioned rodent model of PD, we demonstrate that beta oscillations are inappropriately exaggerated, compared with controls, in a brain-state-dependent manner after chronic dopamine loss. Exaggerated beta oscillations are expressed at the levels of single neurons and small neuronal ensembles, and are focally present and spatially distributed within STN. They are also expressed in synchronous population activities, as evinced by oscillatory local field potentials, in STN and cortex. Excessively synchronized beta oscillations reduce the information coding capacity of STN neuronal ensembles, which may contribute to parkinsonian motor impairment. Acute disruption of dopamine transmission in control animals with antagonists of D1/D2 receptors did not exaggerate STN or cortical beta oscillations. Moreover, beta oscillations were not exaggerated until several days after 6-hydroxydopamine injections. Thus, contrary to predictions, abnormally amplified beta oscillations in cortico-STN circuits do not result simply from an acute absence of dopamine receptor stimulation, but are instead delayed sequelae of chronic dopamine depletion. Targeting the plastic processes underlying the delayed emergence of pathological beta oscillations after continuing dopaminergic dysfunction may offer considerable therapeutic promise.

Parkinsonian Beta Oscillations in the External Globus Pallidus and Their Relationship with Subthalamic Nucleus Activity

Inappropriately synchronized beta (β) oscillations (15–30 Hz) in the subthalamic nucleus (STN) accompany movement difficulties in idiopathic Parkinsons disease (PD). The cellular and network substrates underlying these exaggerated β oscillations are unknown but activity in the external globus pallidus (GP), which forms a candidate pacemaker network with STN, might be of particular importance. Using a clinically relevant rat model of PD, we demonstrate that oscillatory activity in GP neuronal networks becomes excessively and selectively synchronized at β frequencies in a spatially widespread and brain state-dependent manner after lesion of dopamine neurons. Although synchronization of GP unit activity increased by almost 100-fold during β oscillations, the mean firing rate of GP neurons decreased compared with controls. Importantly, in parkinsonian animals, two main types of GP neuron were identified according to their distinct and inversely related firing rates and patterns. Moreover, neurons of the same type tended to fire together, with small phase differences, whereas different types of neuron tended not to do so. This functional dichotomy in temporal coupling persisted across extreme brain states, suggesting that maladaptive interactions are dominated by hardwiring. Finally, the precisely timed discharges of GP and STN neurons indicated that rhythmic sequences of recurrent excitation and inhibition in the STN-GP network, and lateral inhibition between GP neurons, could actively support abnormal β oscillations. We propose that GP neurons, by virtue of their spatiotemporal synchronization, widespread axon collaterals and feed-back/feed-forward mechanisms, are well placed to orchestrate and propagate exaggerated β oscillations throughout the entire basal ganglia in PD.

Patterns of Bidirectional Communication between Cortex and Basal Ganglia during Movement in Patients with Parkinson Disease

Cortico-basal ganglia networks are considered to comprise several parallel and mostly segregated loops, where segregation is achieved in space through topographic connectivity. Recently, it has been suggested that functional segregation may also be achieved in the frequency domain, by selective coupling of related activities at different frequencies. So far, however, any coupling across frequency in the human has only been modeled in terms of unidirectional influences, a misplaced assumption given the looped architecture of the basal ganglia, and has been considered in static terms. Here, we investigate the pattern of bidirectional coupling between mesial and lateral cortical areas and the subthalamic nucleus (STN) at rest and during movement, with and without pharmacological dopaminergic input, in patients with Parkinsons disease. We simultaneously recorded scalp electroencephalographic activity and local field potentials from depth electrodes and deduced patterns of directed coherence between cortical and STN levels across three frequency bands [sub-β (3–13 Hz), β (14–35 Hz), γ (65–90 Hz)] in the different states. Our results show (1) asymmetric bidirectional coupling between STN and both mesial and lateral cortical areas with greater drives from cortex to STN at frequencies <35 Hz, (2) a drop of β band coupling driven from mesial cortex to STN during movement, and (3) an increase in symmetrical bidirectional drives between STN and mesial cortex and in lateral cortical drive to STN in the γ band after dopaminergic therapy. The results confirm a bidirectional pattern of cortico-basal ganglia communication that is differentially patterned across frequency bands and changes with movement and dopaminergic input.

Intra-operative recordings of local field potentials can help localize the subthalamic nucleus in Parkinson's disease surgery

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can be a highly effective treatment for Parkinsons disease (PD). However, therapeutic efficacy is limited by difficulties in consistently and correctly targeting this nucleus. Increasing evidence suggests that there is abnormal synchronization of beta frequency band activity (approximately 20 Hz) in the STN of PD patients, as reflected in the oscillatory nature of the local field potential (LFP). We hypothesized that an increase in the power of the LFP beta activity may provide intra-operative confirmation of STN targeting in patients undergoing STN implantation for the treatment of advanced PD. Accordingly, we recorded LFPs from the four contacts of DBS electrodes as the latter were advanced in 2 mm steps from a point 4-6 mm above the intended surgical target point in the STN, to a point 4 mm below this. Contacts were configured to give three bipolar recordings of LFPs. These were analyzed on 16 sides in 9 patients. The power in the 13-35 Hz band recorded at the lowest contact pair underwent a steep but focal increase during electrode descent. The depth of the peak beta activity showed excellent agreement with the level of the intra-operative clinical stun effect (k coefficient = 0.792). The depth of peak beta activity also showed 100% specificity and 100% sensitivity for placement within STN in comparison to pre- and Post-operative stereotactic MRI. Functional physiological localization of STN by the on-line spectral analysis of LFPs is quick to perform and may provide information directly relevant to the position of the electrode contact actually used for DBS.

Alpha oscillations in the pedunculopontine nucleus correlate with gait performance in parkinsonism

The pedunculopontine nucleus, a component of the reticular formation, is topographically organized in animal models and implicated in locomotor control. In Parkinsons disease, pedunculopontine nucleus stimulation is an emerging treatment for gait freezing. Local field potentials recorded from pedunculopontine nucleus electrodes in such patients have demonstrated oscillations in the alpha and beta frequency bands, reactive to self-paced movement. Whether these oscillations are topographically organized or relevant to locomotion is unknown. Here, we recorded local field potentials from the pedunculopontine nucleus in parkinsonian patients during rest and unconstrained walking. Relative gait speed was assessed with trunk accelerometry. Peaks of alpha power were present at rest and during gait, when they correlated with gait speed. Gait freezing was associated with attenuation of alpha activity. Beta peaks were less consistently observed across rest and gait, and did not correlate with gait speed. Alpha power was maximal in the caudal pedunculopontine nucleus region and beta power was maximal rostrally. These results indicate a topographic distribution of neuronal activity in the pedunculopontine nucleus region and concur with animal data suggesting that the caudal subregion has particular relevance to gait. Alpha synchronization, proposed to suppress ‘task irrelevant’ distraction, has previously been demonstrated to correlate with performance of cognitive tasks. Here, we demonstrate a correlation between alpha oscillations and improved gait performance. The results raise the possibility that stimulation of caudal and rostral pedunculopontine nucleus regions may differ in their clinical effects.

Task-related differential dynamics of EEG alpha- and beta-band synchronization in cortico-basal motor structures

Movement‐related processing results in the modulation of neuronal synchronization over several electroencephalography (EEG) frequency ranges, including alpha‐ (8–12 Hz) and beta‐band (14–30 Hz). Whether modulation patterns differ across sites within the motor system remains unclear, but could denote how information is conveyed across the cortico‐basal network. We therefore compared the event‐related synchronization/desynchronization (ERS/ERD) in recordings from the scalp, basal ganglia and thalamic structures during a motor task.

Reciprocal interactions between oscillatory activities of different frequencies in the subthalamic region of patients with Parkinson's disease.

Synchronization of neuronal activity evident in the local field potential (LFP) recorded in the subthalamic region of patients with Parkinsons disease occurs at low frequencies (< 30 Hz) and, in some patients following treatment with levodopa, at high frequencies between 65 and 85 Hz. Here we investigate the functional relationship between these different activities by determining whether spontaneous fluctuations in their strength are correlated across time. To this end, we analysed recordings of LFPs from macroelectrodes inserted in the subthalamic area of 16 patients with Parkinsons disease, after treatment with anti‐parkinsonian medication. Time‐evolving autospectra of LFPs with significant 65–85 Hz peaks (from 21 sides) were computed and correlations between frequency components determined over time. LFP activity in the 5–32 Hz band was significantly negatively correlated with that in the 65–85 Hz band in data averaged across all 21 sides, as well as in 15 (71%) of the individual records. Negative correlations were relatively selective for interactions between these frequency bands and occurred over time epochs of as little as 40 s. They occurred about 50 min after levodopa and were recorded concurrently with contralateral levodopa‐induced dyskinesias in all but four cases. Positive correlations were not seen between activities in the 5–32 Hz and 65–85 Hz bands. The spontaneous negative correlations suggest a reciprocal relationship between population synchrony in the high‐ and low‐frequency ranges, and raise the possibility that spontaneous fluctuations in the balance between these activities may contribute to levodopa‐induced dyskinesias.

Resonance in subthalamo-cortical circuits in Parkinson's disease

Neuronal activity within and across the cortex and basal ganglia is pathologically synchronized, particularly at ∼ 20 Hz in patients with Parkinsons disease. Defining how activities in spatially distributed brain regions overtly synchronize in narrow frequency bands is critical for understanding disease processes like Parkinsons disease. To address this, we studied cortical responses to electrical stimulation of the subthalamic nucleus (STN) at various frequencies between 5 and 30 Hz in two cohorts of eight patients with Parkinsons disease from two different surgical centres. We found that evoked activity consisted of a series of diminishing waves with a peak latency of 21 ms for the first wave in the series. The cortical evoked potentials (cEPs) averaged in each group were well fitted by a damped oscillator function (r ≥0.9, P < 0.00001). Fits suggested that the natural frequency of the subthalamo-cortical circuit was around 20 Hz. When the system was forced at this frequency by stimulation of the STN at 20 Hz, the undamped amplitude of the modelled cortical response increased relative to that with 5 Hz stimulation in both groups (P ≤ 0.005), consistent with resonance. Restoration of dopaminergic input by treatment with levodopa increased the damping of oscillatory activity (as measured by the modelled damping factor) in both patient groups (P ≤0.001). The increased damping would tend to limit resonance, as confirmed in simulations. Our results show that the basal ganglia–cortical network involving the STN has a tendency to resonate at ∼ 20 Hz in Parkinsonian patients. This resonance phenomenon may underlie the propagation and amplification of activities synchronized around this frequency. Crucially, dopamine acts to increase damping and thereby limit resonance in this basal ganglia–cortical network.

Parkinsonian impairment correlates with spatially extensive subthalamic oscillatory synchronization.

The local strength of pathological synchronization in the region of the subthalamic nucleus (STN) is emerging as a possible factor in the motor impairment of Parkinsons Disease (PD). In particular, correlations have been repeatedly demonstrated between treatment-induced suppressions of local oscillatory activity in the beta frequency band and improvements in motor performance. However, a mechanistic role for beta activity is brought into question by the difficulty in showing a correlation between such activity at rest and the motor deficit in patients withdrawn from medication. Here we recorded local field potential (LFP) activity from 36 subthalamic regions in 18 patients undergoing functional neurosurgery for the treatment of PD. We recorded directly from the contacts of the deep brain stimulation (DBS) electrodes as they were introduced in successive 2 mm steps, and assessed phase coherence as a measure of spatially extended, rather than local, oscillatory synchronization. We found that phase coherence in the beta frequency band correlated with the severity of Parkinsonian bradykinesia and rigidity, both in the limbs and axial body. Such correlations were frequency and site specific in so far as they were reduced when the lowermost contact of the DBS electrode was above the dorsal STN. Correlations with limb tremor occurred at sub-beta band frequencies and were more lateralized than those between beta activity and limb bradykinesia and rigidity. Phase coherence could account for up to ∼25% of the variance in motor scores between sides and patients. These new data suggest that the strength of spatially extended oscillatory synchronization, as well as the strength of local synchronization, may be worthwhile incorporating into modelling studies designed to inform surgical targeting, post-operative stimulation parameter selection and closed-loop stimulation regimes in PD. In addition, they strengthen the link between pathological synchronization and the different motor features of Parkinsonism.