Manuel Alegre

Coupling between Beta and High-Frequency Activity in the Human Subthalamic Nucleus May Be a Pathophysiological Mechanism in Parkinson's Disease

In Parkinsons disease (PD), the oscillatory activity recorded from the basal ganglia shows dopamine-dependent changes. In the “off” parkinsonian motor state, there is prominent activity in the beta band (12–30 Hz) that is mostly attenuated after dopaminergic therapy (“on” medication state). The on state is also characterized by activity in the gamma (60–80 Hz) and high-frequency (300 Hz) bands that is modulated by movement. We recorded local field potentials from a group of 15 PD patients (three females) treated with bilateral deep brain stimulation of the subthalamic nucleus, using a high sampling rate (2 kHz) and filters suitable to study high-frequency activity (0.3–1000 Hz). We observed high-frequency oscillations (HFOs) in both the off and on motor states. In the off state, the amplitude of the HFOs was coupled to the phase of the abnormal beta activity. The beta-coupled HFOs showed little or even negative movement-related changes in amplitude. Moreover, the degree of movement-related modulation of the HFOs correlated negatively with the rigidity/bradykinesia scores. In the on motor state, the HFOs were liberated from this beta coupling, and they displayed marked movement-related amplitude modulation. Cross-frequency interactions between the phase of slow activities and the amplitude of fast frequencies have been attributed an important role in information processing in cortical structures. Our findings suggest that nonlinear coupling between frequencies may not only be a physiological mechanism (as shown previously) but also that it may participate in the pathophysiology of parkinsonism.

Independent component analysis as a tool to eliminate artifacts in EEG: A quantitative study

Summary Independent component analysis (ICA) is a novel technique that calculates independent components from mixed signals. A hypothetical clinical application is to remove artifacts in EEG. The goal of this study was to apply ICA to standard EEG recordings to eliminate well-known artifacts, thus quantifying its efficacy in an objective way. Eighty samples of recordings with spikes and evident artifacts of electrocardiogram (EKG), eye movements, 50-Hz interference, muscle, or electrode artifact were studied. ICA components were calculated using the Joint Approximate Diagonalization of Eigen-matrices (JADE) algorithm. The signal was reconstructed excluding those components related to the artifacts. A normalized correlation coefficient was used as a measure of the changes caused by the suppression of these components. ICA produced an evident clearing-up of signals in all the samples. The morphology and the topography of the spike were very similar before and after the removal of the artifacts. The correlation coefficient showed that the rest of the signal did not change significantly. Two examiners independently looked at the samples to identify the changes in the morphology and location of the discharge and the artifacts. In conclusion, ICA proved to be a useful tool to clean artifacts in short EEG samples, without having the disadvantages associated with the digital filters. The distortion of the interictal activity measured by correlation analysis was minimal.

Movement-related changes in oscillatory activity in the human subthalamic nucleus : ipsilateral vs. contralateral movements

A voluntary movement is accompanied by a series of changes in neuronal oscillatory activity in the subthalamic nucleus (STN). These changes can be recorded through electrodes implanted for deep brain stimulation to treat Parkinsons disease in the time interval between the surgery and the internalization of the connections to the batteries. Both baseline activity and movement‐related changes are different in the ‘on’ and ‘off’ medication motor states. In the ‘off’ state a low frequency activity in the alpha–beta range (8–25 Hz) that dominates the spectrum is interrupted during the movement, while in the ‘on’ state baseline frequencies are higher and a peri‐movement gamma increase (70–80 Hz) is usually observed. Similar changes have been described with electrocorticographic recordings over the primary motor cortex but the gamma increase was only present during contralateral movements. We compared ipsi‐ and contralateral movement‐related changes in STN activity, using a time–frequency analysis of the recordings obtained simultaneously in both STN and the scalp (electroencephalography) during right and left hand movements. The movement‐related changes observed in the STN in the ‘on’ and the ‘off’ states were similar to those described previously in terms of predominant frequency bands, but we found bilateral changes in the STN during movements of either hand. A contralateral earlier start of the beta STN changes was mostly observed when the moving hand corresponded to the less‐affected side, irrespective of hand dominance. These results suggest that movement‐related activity in the STN has, by and large, a bilateral representation and probably reflects cortical input.

Beta electroencephalograph changes during passive movements: sensory afferences contribute to beta event-related desynchronization in humans

Non-phase-locked beta oscillatory changes during passive movements were studied in six healthy volunteers, and compared with those observed in a similar group during ballistic movements. Passive movements consisted of brisk wrist extensions done with the help of a pulley system. Changes in the beta band were determined by means of wavelet and Gabor transforms, and compared statistically with a pre-movement period. In this paradigm, a marked beta energy loss (event-related desynchronization, ERD) was present after the beginning of the movement, followed by a beta energy increase (event-related synchronization, ERS). The ERD/ERS was similar to that observed during ballistic movements, but without pre-movement components. Although both changes were maximal in the contralateral central electrode, the beta ERD showed a more bilateral topography. These findings suggest that afferent proprioceptive inputs may play a role in the final part of the beta ERD observed during voluntary movements.

Independent component analysis removing artifacts in ictal recordings

Summary:  Purpose: Independent component analysis (ICA) is a novel algorithm able to separate independent components from complex signals. Studies in interictal EEG demonstrate its usefulness to eliminate eye, muscle, 50‐Hz, electrocardiogram (ECG), and electrode artifacts. The goal of this study was to evaluate the usefulness of ICA in removing artifacts in ictal recordings with a known EEG onset.

Gamma band activity in an auditory oddball paradigm studied with the wavelet transform.

OBJECTIVES To examine the characteristics of evoked and induced gamma band oscillatory responses occurring during P300 development in an auditory oddball paradigm. METHODS A time-frequency analysis method was applied to an auditory oddball paradigm in 7 healthy subjects. This method combines a multiresolution wavelet algorithm for signal extraction and the Gabor transform to represent the temporal evolution of the selected frequency components. Phase-locked or evoked activity and also non-phase-locked activity were computed for both standard and target stimuli. RESULTS The gamma band frequency components differed between target and non-target stimuli processing. The study showed an early and mainly phase-locked oscillatory response appearing around 26--28 ms after both standard and target stimuli onset. This response showed a spectral peak around 44 Hz for both stimuli. A late oscillatory activity peaking at 37 Hz with a latency around 360 ms was observed appearing only for target stimuli. The latency of this late oscillatory activity had a high correlation (P=0.002) to the latency of the P300 wave. CONCLUSIONS EEG signal analysis with wavelet transform allows the identification of an early oscillatory cortical response in the gamma frequency range, as well as a late P300-related response.

Frontal and central oscillatory changes related to different aspects of the motor process: a study in go/no-go paradigms

We studied alpha and beta EEG oscillatory changes in healthy volunteers during two different auditory go/no-go paradigms, in order to investigate their relationship with different components of the motor process. In the first paradigm (S2-centered), the initial tone (S1) was constant (warning), and the second tone (S2) indicated the subject whether to move or not. In the second paradigm (S1-centered), S1 indicated whether to move or not, while S2 just indicated the timing of the movement. A medial frontal beta energy increase was found in all conditions after the stimulus that forces the subject to decide whether to move or not (S1 or S2 depending on the paradigm). In both go conditions, a central alpha and beta energy decrease began after the go decision, reaching minimum values during the movement; it was followed by a beta post-movement increase, limited to the central contralateral area. In the no-go conditions, a marked fronto-central beta synchronization appeared after the decision not to move. In conclusion, our study was able to dissociate the beta oscillatory changes related to movement preparation and execution (central decrease/increase) from those associated with decision-making (medial frontal increase) and motor inhibition (fronto-central increase).

Parkinson's Disease, the Subthalamic Nucleus, Inhibition, and Impulsivity

Although Parkinsons disease (PD) is primarily considered a disorder of initiation of actions, patients also have deficits in inhibitory control, both in the motor and cognitive domains. Impulse control disorders, which can develop in association with dopaminergic medication in a small proportion of patients with PD, are the symptoms most commonly considered as representing inhibitory deficits. However, there is now also a body of evidence suggesting a role for the subthalamic nucleus (STN), which is ordinarily hyperactive in PD, in inhibitory control. Here, we review evidence from animal studies, imaging studies, and investigations recording STN activity intra‐ or perioperatively in patients with PD having surgery for DBS of the STN (STN‐DBS). We also highlight relevant hypotheses about the role of the STN and consider evidence from studies that have examined the effect of STN‐DBS in patients with PD on performance of experimental tasks requiring inhibition of prepotent or habitual responses or decision making under conflict, as well as the psychiatric side effects of STN‐DBS. Though the results are not always consistent, nevertheless, this body of evidence supports the role of the STN in inhibitory and executive control.

Successful Thalamic Deep Brain Stimulation for Orthostatic Tremor

We report a patient with severe orthostatic tremor (OT) unresponsive to pharmacological treatments that was successfully controlled with thalamic (Vim, ventralis intermedius nucleus) deep brain stimulation (DBS) over a 4‐year period. Cortical activity associated with the OT revealed by EEG back‐averaging and fluoro‐deoxi‐glucose PET were also suppressed in parallel with tremor arrest. This case suggests that Vim‐DBS may be a useful therapeutic approach for patients highly disabled by OT.

Ketamine-Induced Oscillations in the Motor Circuit of the Rat Basal Ganglia

Oscillatory activity can be widely recorded in the cortex and basal ganglia. This activity may play a role not only in the physiology of movement, perception and cognition, but also in the pathophysiology of psychiatric and neurological diseases like schizophrenia or Parkinsons disease. Ketamine administration has been shown to cause an increase in gamma activity in cortical and subcortical structures, and an increase in 150 Hz oscillations in the nucleus accumbens in healthy rats, together with hyperlocomotion. We recorded local field potentials from motor cortex, caudate-putamen (CPU), substantia nigra pars reticulata (SNr) and subthalamic nucleus (STN) in 20 awake rats before and after the administration of ketamine at three different subanesthetic doses (10, 25 and 50 mg/Kg), and saline as control condition. Motor behavior was semiautomatically quantified by custom-made software specifically developed for this setting. Ketamine induced coherent oscillations in low gamma (50 Hz), high gamma (80 Hz) and high frequency (HFO, 150 Hz) bands, with different behavior in the four structures studied. While oscillatory activity at these three peaks was widespread across all structures, interactions showed a different pattern for each frequency band. Imaginary coherence at 150 Hz was maximum between motor cortex and the different basal ganglia nuclei, while low gamma coherence connected motor cortex with CPU and high gamma coherence was more constrained to the basal ganglia nuclei. Power at three bands correlated with the motor activity of the animal, but only coherence values in the HFO and high gamma range correlated with movement. Interactions in the low gamma band did not show a direct relationship to movement. These results suggest that the motor effects of ketamine administration may be primarily mediated by the induction of coherent widespread high-frequency activity in the motor circuit of the basal ganglia, together with a frequency-specific pattern of connectivity among the structures analyzed.