Friederike U. Hohlefeld

Long-range temporal correlations in the subthalamic nucleus of patients with Parkinson’s disease

Neuronal activity in the subthalamic nucleus (STN) of patients with Parkinson’s disease (PD) is characterised by excessive neuronal synchronization, particularly in the beta frequency range. However, less is known about the temporal dynamics of neuronal oscillations in PD. In this respect long‐range temporal correlations (LRTC) are of special interest as they quantify the neuronal dynamics on different timescales and have been shown to be relevant for optimal information processing in the brain. While the presence of LRTC has been demonstrated in cortical data, their existence in deep brain structures remains an open question. We investigated (i) whether LRTC are present in local field potentials (LFP) recorded bilaterally from the STN at wakeful rest in ten patients with PD after overnight withdrawal of levodopa (OFF) and (ii) whether LRTC can be modulated by levodopa treatment (ON). Detrended fluctuation analysis was utilised in order to quantify the temporal dynamics in the amplitude fluctuations of LFP oscillations. We demonstrated for the first time the presence of LRTC (extending up to 50 s) in the STN. Importantly, the ON state was characterised by significantly stronger LRTC than the OFF state, both in beta (13–35 Hz) and high‐frequency (> 200 Hz) oscillations. The existence of LRTC in subcortical structures such as STN provides further evidence for their ubiquitous nature in the brain. The weaker LRTC in the OFF state might indicate limited information processing in the dopamine‐depleted basal ganglia. The present results implicate LRTC as a potential biomarker of pathological neuronal processes in PD.

Functional and effective connectivity in subthalamic local field potential recordings of patients with Parkinson’s disease

In Parkinsons disease (PD) levodopa-associated changes in the power and long-range temporal correlations of beta oscillations have been demonstrated, yet the presence and modulation of genuine connectivity in local field potentials (LFP) recorded from the subthalamic nucleus (STN) remains an open question. The present study investigated LFP recorded bilaterally from the STN at wakeful rest in ten patients with PD after overnight withdrawal of levodopa (OFF) and after a single dose levodopa administration (ON). We utilized connectivity measures being insensitive to volume conduction (functional connectivity: non-zero imaginary part of coherency; effective connectivity: phase-slope index). We demonstrated the presence of neuronal interactions in the frequency range of 10-30 Hz in STN-LFP without a preferential directionality of interactions between different contacts along the electrode tracks. While the direction of neuronal interactions per se was preserved after levodopa administration, functional connectivity and the ventral-dorsal information flow were modulated by medication. The OFF-ON differences in functional connectivity were correlated with the levodopa-induced improvement in clinical Unified Parkinsons Disease Rating Scale scores. We hypothesize that regional neuronal interactions, as reflected in STN-LFP connectivity, might represent a basis for the intra-nuclear spatial specificity of deep brain stimulation. Moreover, our results suggest the potential use of volume conduction-insensitive measures of connectivity in STN-LFP as a marker of clinical motor symptoms in PD.

Visual stimuli evoke rapid activation (120 ms) of sensorimotor cortex for overt but not for covert movements.

Overt and covert movements (e.g., motor imagery) have been frequently demonstrated to engage common neuronal substrates in the motor system. However, it is an open question whether this similarity is also present during early stages of stimulus-processing. We utilized the high temporal resolution of multi-channel electroencephalography (EEG) in order to test whether the prior action intention (overt vs. covert movements) differentially modulates early stimulus-processing stages in the cortical sensorimotor system. The subjects performed overt or covert movements contingent upon an instructive visual stimulus (indicating left or right hand performance). We introduced a novel measure, LRPrect, calculated as Lateralized Readiness Potentials from rectified EEG signals. This measure overcomes a problem related to the EEG signal variability due to polarity differences in the spatial distribution of neuronal sources. The LRPrect showed an activation already at 120 ms after stimulus onset (latN120) focally over sensorimotor cortices contralateral to the upcoming hand movement, yet only for overt but not covert movements. Thus the prior action intention differentially routes early stimulus-processing into the sensorimotor system, which might contribute to significantly different behavioral outcomes, i.e., movement generation or inhibition. The present results have implications for studies of motor inhibition and action intention.

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

Parkinsons 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.

Modulation of cortical neural dynamics during thalamic deep brain stimulation in patients with essential tremor.

Although thalamic deep brain stimulation is an effective treatment for patients with essential tremor, little is known about its effect on cortical neural dynamics. Therefore, we investigated long-range temporal correlations and spectral power in electroencephalographic recordings of patients during OFF versus ON bilateral thalamic deep brain stimulation in comparison with healthy controls. Cortical dynamics were analyzed in the range of 6–30 Hz. We found the presence of long-range temporal correlations up to 20 s in patients and controls. Thalamic deep brain stimulation was associated with increased long-range temporal correlations in the high beta band (21–30 Hz) and decreased power in the low beta band (13–20 Hz) compared with OFF stimulation and healthy controls. Long-range temporal correlations in the 6–10 Hz range were increased with OFF stimulation compared with the controls. Importantly, deep brain stimulation-induced changes in long-range temporal correlations within 6–10 Hz and in the beta ranges (13–20, 21–30 Hz) were correlated with OFF–ON changes in the tremor severity and with the disease duration, respectively. The differential reactivity of long-range temporal correlations and spectral power to deep brain stimulation might suggest that both measures reflect distinct aspects of cortical dynamics and might represent biomarkers for stimulation-induced modulations of neural dynamics in electroencephalography. The fact that long-range temporal correlations, but not spectral power, were correlated with clinical information might suggest long-range temporal correlations as a potential marker for disease severity in essential tremor.

Covert movements trigger repetition suppression of electroencephalography in sensorimotor cortex.

‘Repetition suppression’ (RS) denotes the decrease of neural responses to repeated external sensory stimuli. Weshowed that RS can be also triggered by internal processes alone. When individuals perform repetitive covert movements, that is, motor imagery or quasi-movements, both of which are associated with pericentral cortical activity without muscle activations, there was asignificant recovery of electroencephalographic oscillations over sensorimotor cortices back to resting baseline level. After 58 s of task performance only 20% of&agr;and 5% of &bgr; suppressions remained (overt movements: 34% remaining in &agr;, complete recovery in &bgr;). This result suggests that various, possibly all, repeated cerebral activations are associated with RS, presumably reflecting the adaptation to stereotyped activation in neuralnetworks.

The influence of spontaneous brain oscillations on apparent motion perception

A good example of inferential processes in perception is long-range apparent motion (AM), the illusory percept of visual motion that occurs when two spatially distinct stationary visual objects are presented in alternating sequence. The AM illusion is strongest at presentation frequencies around 3 Hz. At lower presentation frequencies, the percept varies from trial to trial between AM and sequential alternation, while at higher frequencies perception varies between AM and two simultaneously flickering objects. Previous studies have demonstrated that prestimulus alpha oscillations explain trial-to-trial variability in detection performance for visual stimuli presented at threshold. In the present study, we investigated whether fluctuations of prestimulus alpha oscillations can also account for variations in AM perception. Prestimulus alpha power was stronger when observers reported AM perception in subsequent trials with low presentation frequencies, while at high presentation frequencies there were no significant differences in alpha power preceding AM and veridical flicker perception. Moreover, when observers perceived AM the prestimulus functional connectivity between frontal and occipital channels was increased in the alpha band, as revealed by the imaginary part of coherency, which is insensitive to artefacts from volume conduction. Dynamic causal modelling of steady-state responses revealed that the most likely direction of this fronto-occipital connectivity was from frontal to occipital sources. These results point to a role of ongoing alpha oscillations in the inferential process that gives rise to the perception of AM and suggest that fronto-occipital interactions bias perception towards internally generated predictions.

Effect of complete stimulus predictability on P3 and N2 components: an electroencephalographic study.

In everyday life one may encounter both unpredictable and self-initiated, hence anticipated, events. Here, we analyzed the effects of self-initiated auditory stimulus presentation on P3 and N2 components in an oddball paradigm. If the stimulus sequence was fully self-determined, both components were attenuated in comparison with computer-controlled representation. In contrast, both components were increased when only the stimulus onset was self-initiated, yet the forthcoming stimulus type was unknown. We hypothesize that predictive forward models offer an unifying explanation for the modulation of both P3 and N2 through: (a) attenuation of neuronal responses to anticipated stimuli contingent on ones own motor action and (b) enhancement of responses in case of incongruity between an anticipated action effect and the actual perceptual consequences.