Gamma activity and reactivity in human thalamic local field potentials.

Depth recordings in patients with Parkinson's disease on dopaminergic therapy have revealed a tendency for oscillatory activity in the basal ganglia that is sharply tuned to frequencies of approximately 70 Hz and increases with voluntary movement. It is unclear whether this activity is essentially physiological and whether it might be involved in arousal processes. Here we demonstrate an oscillatory activity with similar spectral characteristics and motor reactivity in the human thalamus. Depth signals were recorded in 29 patients in whom the ventral intermediate or centromedian nucleus were surgically targeted for deep brain stimulation. Thirteen patients with four different pathologies showed sharply tuned activity centred at approximately 70 Hz in spectra of thalamic local field potential (LFP) recordings. This activity was modulated by movement and, critically, varied over the sleep-wake cycle, being suppressed during slow wave sleep and re-emergent during rapid eye movement sleep, which physiologically bears strong similarities with the waking state. It was enhanced by startle-eliciting stimuli, also consistent with modulation by arousal state. The link between this pattern of thalamic activity and that of similar frequency in the basal ganglia was strengthened by the finding that fast thalamic oscillations were lost in untreated parkinsonian patients, paralleling the behaviour of this activity in the basal ganglia. Furthermore, there was sharply tuned coherence between thalamic and pallidal LFP activity at approximately 70 Hz in eight out of the 11 patients in whom globus pallidus and thalamus were simultaneously implanted. Subcortical oscillatory activity at approximately 70 Hz may be involved in movement and arousal.

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 Parkinson's disease (PD), but its mechanism of action is unclear. Exaggerated oscillatory synchronization in the beta (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 beta 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 beta activity for 12 s after the end of stimulation and a decrease in motor cortical-STN coherence in the beta band over the same time period. The reduction in LFP beta activity correlated with the movement amplitude during a simple motor task, so that a smaller amount of beta 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 beta activity in PD.

Movement-related synchronization of gamma activity is lateralized in patients with dystonia.

There is evidence for synchronization at frequencies both under 30 Hz and over 60-80 Hz in the so-called gamma frequency band in patients with Parkinson's disease (PD). Gamma activity increases after dopaminergic therapy and during voluntary movement, suggesting that it might be physiological and relate to motor processing in the basal ganglia (BG). We recorded local field potential (LFP) activity during a choice reaction time task in 11 patients with dystonia undergoing implantation of the internal globus pallidus for therapeutic stimulation. The spectral content of the LFP was averaged with respect to movement onset over 6-11 Hz, 18-25 Hz and 60-80 Hz, separately for responses ipsilateral and contralateral to movement. There was a perimovement increase in 60-80 Hz activity in the LFP, but only contralateral to movement. In contrast, low-frequency LFP activity decreased symmetrically during movement. This occurred earlier in the 18-25 Hz band than in the 6-11 Hz band, and was followed by a postmovement increase in oscillatory activity in the 18-25 Hz band that was contralateral to movement. The presence of a lateralized movement-related increase in gamma activity in the BG of patients with dystonia, similar to that recorded in patients with treated PD, suggests that this may be a residual feature of normal BG function. Moreover, the results provide further support for functional distinctions between BG oscillatory activities of different frequency.

Amplitude modulation of oscillatory activity in the subthalamic nucleus during movement.

Depth recordings in patients with Parkinson's disease (PD) have demonstrated exaggerated local field potential (LFP) activity at frequencies between 10 and 30 Hz in the subthalamic nucleus (STN). This activity is modulated prior to single phasic movements, possibly as part of the feedforward organization of incipient voluntary movement, and after single phasic movements, as a consequence of afferent feedback processes. Here we test the hypothesis that this activity is also modulated during repetitive movements, reflecting a role in ongoing performance. Accordingly, we recorded LFP activity from the contralateral STN of seven patients with PD withdrawn from anti-parkinsonian medication while they performed repetitive index finger to thumb taps. Cross-correlograms of LFP activity at different frequencies in the 10-30 Hz band with finger position showed that LFP activity was modulated in amplitude by finger tapping. The modulation was higher at the beginning of each recording when tapping performance was better, and diminished as tapping became more bradykinetic over time. The best modulations were seen over those frequencies that were maximal in the power spectrum of the corresponding LFP, and for a given side were most marked at the contact pair that exhibited the highest power at these frequencies. In conclusion, subthalamic activity in the 10-30-Hz band is amplitude modulated during movement. This process fails as bradykinesia increases.

Modulation by dopamine of human basal ganglia involvement in feedback control of movement.

We learn new motor tasks by trial and error, repeating what works best and avoiding past mistakes. To repeat what works best we must register a satisfactory outcome, and in a study [1] we showed the existence of an evoked activity in the basal ganglia that correlates with accuracy of task performance and is associated with reiteration of successful motor parameters in subsequent movements. Here we report evidence that the signaling of positive trial outcome relies on dopaminergic input to the basal ganglia, by recording from the subthalamic nucleus (STN) in patients with nigrostriatal denervation due to Parkinson's Disease (PD) who have undergone functional neurosurgery. Correlations between subthalamic evoked activities and trial accuracy were weak and behavioral performance remained poor while patients were untreated; however, both improved after the dopamine prodrug levodopa was re-introduced. The results suggest that the midbrain dopaminergic system may be important, not only in signaling explicit positive outcomes or rewards in tasks requiring choices between options [2,3], but also in trial-to-trial learning and in reinforcing the selection of optimal parameters in more automatic motor control.

Premovement activities in the subthalamic area of patients with Parkinson's disease and their dependence on task.

Movement preparation and execution are associated with a reduction in oscillatory synchrony over 6-35 Hz (event-related desynchronization; ERD) and increases in oscillatory synchrony at higher frequencies (event-related synchronization; ERS) in the human parkinsonian subthalamic nucleus (STN). The timing of the ERD < 35 Hz in STN correlates with, but precedes, the timing of voluntary movement, in line with a role in motor processing. Here, we explore how directly the synchrony manifest in local field potential (LFP) activities depends on the details of motor processing. To this end, we recorded local field potentials from the STN area of parkinsonian subjects while they performed internally paced single movements or double movements with one hand. Analysis was limited to time periods that were unequivocally premovement, so as to avoid the confounding effects of sensory afferance during movement. LFP power differed from baseline activity as early as 2.1-1.1 s prior to movement over 6-18 Hz and 56-70 Hz. However, only the early changes in LFP power in the 56-70 Hz band depended on task type. Later on, within 0.5 s of the forthcoming movement, the behaviour of both the 6-18 and 56-70 Hz bands differed according to movement type. In addition, a change was seen in LFP activity over 23-35 Hz, although the ERD in this band remained similar across movement types. The findings further implicate the human STN in the feedforward organization of movement in premotor circuits. Different aspects of this organization may be preferentially reflected in changes in synchrony at different frequencies.

Dopaminergic therapy promotes lateralized motor activity in the subthalamic area in Parkinson's disease.

Treatment of patients with Parkinson's disease with levodopa has profound effects on both movement and the pattern of movement-related reactivity in the subthalamic nucleus (STN), as reflected in the local field potential (LFP). The most striking change is the promotion of reactivity in the gamma frequency band, but it remains unclear whether the latter is itself a pathological feature, possibly associated with levodopa induced dyskinesias, or is primarily physiological. Gamma band reactivity in the cerebral cortex of humans without Parkinson's disease occurs contralateral to movement, so we posited that lateralization of subcortical gamma reactivity should occur following levodopa if the latter restores a more physiological pattern in patients with Parkinson's disease. Accordingly, we studied movement-related changes in STN LFP activity in 11 Parkinson's disease patients (age 59 +/- 2.7 years, three females) while they performed ipsi- and contralateral self-paced joystick movements ON and OFF levodopa. A bilaterally symmetrical gamma band power increase occurred around movement onset in the OFF state. Following levodopa this feature became significantly more pronounced in the subthalamic region contralateral to movement. The physiological nature of this asymmetric pattern of gamma reactivity was confirmed in the STN of two tremor patients without Parkinson's disease. Although levodopa treatment in the Parkinson's disease patients did not lead to lateralization of power suppression at lower frequencies (8-30 Hz), it did increase the degree of power suppression. These findings suggest that dopaminergic therapy restores a more physiological pattern of reactivity in the STN of patients with Parkinson's disease.

Illuminating the BOLD signal: combined fMRI-fNIRS studies.

Functional magnetic resonance imaging (fMRI) is currently combined with electrophysiological methods to identify the relationship between neuronal activity and the blood oxygenation level-dependent (BOLD) signal. Several processes like neuronal activity, synaptic activity, vascular dilation, blood volume and oxygenation changes underlie both response modalities, that is, the electrophysiological signal and the vascular response. However, accessing single process relationships is absolutely mandatory when aiming at a deeper understanding of neurovascular coupling and necessitates studies on the individual building blocks of the vascular response. Combined fMRI and functional near-infrared spectroscopy studies have been performed to validate the correlation of the BOLD signal to the hemodynamic changes in the brain. Here we review the current status of the integration of both technologies and judge these studies in the light of recent findings on neurovascular coupling.

The fast optical signal--robust or elusive when non-invasively measured in the human adult?

Near infrared spectroscopy (NIRS) can detect vascular changes in cerebral cortical tissue elicited by functional stimulation. For some 10 years, another optical signal has been reported to be accessible by NIRS. This signal has been reported to correlate to the electrophysiological response rendering NIRS an exquisite non-invasive approach to investigate neurovascular coupling in the human adult. Due to their typical latency of up to hundreds of milliseconds, these signals have been termed "fast" optical signals and have been postulated to stem from scatter changes in neuronal tissue, as a fingerprint of the electrophysiological response. Here, we utter a less optimistic view on the non-invasive detectability of these changes in the human, motivated by an upper limit signal size estimation, predicting a signal size by orders of magnitude smaller than those previously reported. Also, we discuss the influence of small stimulus correlated movement artifacts potentially mimicking a fast optical signal. Based on invasive studies, we perform an upper limit estimation for changes in intensity and mean time of flight, which can be expected assuming a scatter change in the cerebral cortex while measuring on the surface of the head of an adult subject. Since the resulting numbers are far below those previously reported, we constructed a simple system, which minimizes technical noise. The system allows us to detect rather small intensity changes (2 x 10(-3)%) when averaging over approximately 3000 stimuli. Despite this outstandingly low noise level of the system, we find a reliable change in response to a sub-motor-threshold steady state median nerve stimulation in just one single subject (8 subjects examined, 4 subjects twice). Exceeding the motor threshold leads to large stimulus related artifacts, on a similar time scale and with comparable amplitude as previously reported signals. To check for potential modality specific problems, we next performed a visual stimulation study, avoiding potential motor artifacts. For the steady state visually evoked response, no subject yielded a reliable result (11 subjects examined, 4 subjects twice). The paper discusses these findings by a review of the literature on fast optical signals and their being accessible in the adult human.