Johannes Sarnthein

Different frequencies for different scales of cortical integration: from local gamma to long range alpha/theta synchronization

Cortical activity and perception are not driven by the external stimulus alone; rather sensory information has to be integrated with various other internal constraints such as expectations, recent memories, planned actions, etc. The question is how large scale integration over many remote and size-varying processes might be performed by the brain. We have conducted a series of EEG recordings during processes thought to involve neuronal assemblies of varying complexity. While local synchronization during visual processing evolved in the gamma frequency range, synchronization between neighboring temporal and parietal cortex during multimodal semantic processing evolved in a lower, the beta1 (12-18 Hz) frequency range, and long range fronto-parietal interactions during working memory retention and mental imagery evolved in the theta and alpha (4-8 Hz, 8-12 Hz) frequency range. Thus, a relationship seems to exist between the extent of functional integration and the synchronization-frequency. In particular, long-range interactions in the alpha and theta ranges seem specifically involved in processing of internal mental context, i.e. for top-down processing. We propose that large scale integration is performed by synchronization among neurons and neuronal assemblies evolving in different frequency ranges.

Persistent EEG overactivation in the cortical pain matrix of neurogenic pain patients.

Functional brain imaging of pain over the last years has provided insight into a distributed anatomical matrix involved in pain processing which includes multiple cortical areas. EEG/MEG-based imaging studies have mostly relied on settings of evoked nociception. We report here the spontaneous presence of enhanced activations in the pain matrix of the patient group on the basis of continuous EEG and functional Low Resolution Electromagnetic Tomography (LORETA) from 16 chronic neurogenic pain patients and 16 healthy controls. These overactivations occurred predominantly within the high theta (6-9 Hz) and low beta frequency ranges (12-16 Hz). Theta and beta overactivations were localized to multiple pain-associated areas, primarily to insular (IC), anterior cingulate (ACC), prefrontal, and inferior posterior parietal cortices, as well as to primary (S1), secondary (S2), and supplementary somatosensory (SSA) cortices. After a therapeutic lesion in the thalamus (central lateral thalamotomy, CLT), we followed a subgroup of 6 patients. Twelve months after surgery, activation in cingulate and insular cortices was significantly reduced. The presence of rhythmic processes in multiple, partially overlapping areas of the cortical pain matrix concur with the concept of thalamocortical dysrhythmia (TCD) that predicts increased thalamocortical low and high frequency oscillations ensuing from thalamic desactivation. These spontaneous, ongoing, frequency-specific overactivations may therefore serve as an anatomo-physiological hallmark of the processes underlying chronic neurogenic pain.

Test-retest reliability of resting EEG spectra validates a statistical signature of persons

OBJECTIVE When EEG is recorded in humans, the question arises whether the resting EEG remains stable. We compared the inter-individual variation in spectral observables to the intra-individual stability over more than a year. METHODS We recorded resting EEG in 55 healthy adults with eyes closed. In 20 persons EEG was recorded in a second session with retest intervals 12-40 months. For electrodes AFz, Cz and Pz alpha peak frequency and alpha peak height were transformed into Z-scores. We compared the curve shape of power spectra by first aligning alpha peaks to 10Hz and then regressing spectra pairwise onto each other to calculate a t-value. The t-value and differences of Z-scores for all pairs of sessions were entered into a generalized linear model (GLM) where binary output represents the recognition probability. The results were cross-validated by out-of-sample testing. RESULTS Of the 40 sessions, 35 were correctly matched. The shape of power spectra contributed most to recognition. Out of all 2960 pairwise comparisons 99.5% were correct, with sensitivity 88% and specificity 99.5%. CONCLUSIONS Our statistical apparatus allows to identify those spectral EEG observables which qualify as statistical signature of a person. SIGNIFICANCE The effect of external factors on EEG observables can be contrasted against their normal variability over time.

High thalamocortical theta coherence in patients with neurogenic pain

Patients with severe and chronic neurogenic pain are known to exhibit excess EEG oscillations in the 4- to 9-Hz theta frequency band in comparison with healthy controls. The generators of these excess EEG oscillations are localized in the cortical pain matrix. Since cortex and thalamus are tightly interconnected anatomically, we asked how thalamic activity and EEG are functionally related in these patients. During the surgical intervention in ten patients with neurogenic pain, local field potentials were recorded from the posterior part of the central lateral nucleus (CL). The highest thalamocortical coherence was found in the 4- to 9-Hz theta frequency band (median 7.7 Hz). The magnitude of thalamocortical theta coherence was comparable to the magnitude of EEG coherence between scalp electrode pairs. Median thalamocortical theta coherence was 27%, reached up to 68% and was maximal with frontal midline scalp sites. The observed high thalamocortical coherence underlines the importance of the thalamus for the synchronization of scalp EEG. We discuss the pathophysiology within the framework of a dysrhythmic thalamocortical interplay, which has important consequences for the choice of therapeutic strategy in patients with chronic and severe forms of neurogenic pain.

EEG alpha distinguishes between cuneal and precuneal activation in working memory

In the literature on EEG during working memory (WM), the role of alpha power (8-13 Hz) during WM retention has remained unclear. We recorded EEG while 18 subjects retained sets of consonants in memory for 3 s; setsize (ss4, ss6, ss8) determines memory workload. Theta power (4-8 Hz) increased with workload in all subjects in middle frontal electrodes. Using ICA, the increase in theta could be attributed to one component whose generators were localized by sLORETA in the medial frontal gyrus. Alpha power in parietal electrode Pz showed a mean increase during retention as compared to prestimulus fixation (event-related synchronization, ERS). On an individual basis, alpha power increased with workload in 9 subjects (WL+ group) and decreased in 9 subjects (WL- group). The alpha increased in upper alpha for the WL+ group (mean: 10.4 Hz) and decreased in lower alpha for the WL- group (mean: 8.9 Hz). Time-frequency representations show high alpha power early during retention for the WL+ group and high alpha power late during retention for the WL- group. sLORETA revealed maximal contrast for the WL+ group in the cuneus and for the WL- group in the precuneus. In subjects with WL+, alpha increase in the cuneus may reflect WM maintenance or active inhibition of task-irrelevant areas. In subjects with WL-, alpha decrease in the precuneus may reflect release of inhibition associated with attentional demands. Thus, alpha EEG characterizes two aspects of processing in the same WM task.

High Thalamocortical Theta Coherence in Patients with Parkinson's Disease

Research investigating the pathophysiology of Parkinsons disease (PD) mostly focuses on basal ganglia dysfunction. However, the main output from the basal ganglia is via the thalamus, and corticothalamic feedback constitutes the primary source of synapses in the thalamus. We therefore focus on the thalamocortical interplay. During the surgical intervention in six patients, local field potentials (LFPs) were recorded from pallidal-recipient thalamic nuclei VA and VLa. Simultaneously, EEG was recorded from several sites on the scalp. The highest thalamocortical coherence was found in the theta frequency band (4–9 Hz) with a mean peak frequency of 7.5 Hz. The magnitude of thalamocortical theta coherence was comparable to the magnitude of EEG coherence between scalp electrode pairs. Thalamocortical theta coherence reached 70% and was maximal with frontal scalp sites on both hemispheres. In the 13–20 Hz β frequency band, maximal coherence was comparatively low but localized on the scalp ipsilateral to the site of thalamic LFP recording. The high thalamocortical coherence underlines the importance of thalamic function for the genesis of scalp EEG. We discuss the PD pathophysiology within the framework of dysrhythmic thalamocortical interplay, which has important consequences for the choice of therapeutic strategy in patients with severe forms of PD.

Enhanced frontal low and high frequency power and synchronization in the resting EEG of parkinsonian patients

Oscillatory and coherent EEG activity is increasingly recognized as a fundamental hallmark of cortical integrative functions. We aimed to study deviations from the norm of different resting EEG parameters in Parkinsons disease (PD) patients. We compared spectral parameters of the resting EEG of PD patients (n=24, median age 67 years) to those of healthy controls (n=34, median age 62 years). On average, the patient group exhibited higher spectral power over the frequency range of 2-100 Hz, and the dominant peak was shifted towards lower frequencies. Maximal differences appeared in the 6-9 Hz theta band in all electrodes. Frontal electrodes contributed most to this difference in the 4-6 Hz theta, 12-18 Hz beta and 30-45 Hz gamma bands. On an individual basis, the combination of six spectral power band parameters discriminated between patient and control groups and 72% of all subjects were classified correctly. Using LORETA source analysis, the generators of this power difference were localized to fronto-insulo-temporal cortical areas in the theta and beta bands, and to interhemispheric frontal (supplementary motor area, SMA) and cingulate areas in the 30-45 Hz gamma band. We calculated spectral coherence between electrode pairs in a frontal, central and parietal region of interest (ROI). In the frontal ROI, coherence was enhanced significantly in the patient group in the theta, high beta and gamma bands. In the parietal ROI, patients showed lower coherence around 10 Hz. We demonstrate a deviation from the norm of different resting EEG parameters in PD patients. This evidence can be integrated in the context of a pathophysiological chain reaction initiated in the substantia nigra and resulting in a cortical aberrant dynamics rooted in enhanced dysrhythmic thalamocortical interactions.

Human Intracranial High Frequency Oscillations (HFOs) Detected by Automatic Time-Frequency Analysis

Objectives High frequency oscillations (HFOs) have been proposed as a new biomarker for epileptogenic tissue. The exact characteristics of clinically relevant HFOs and their detection are still to be defined. Methods We propose a new method for HFO detection, which we have applied to six patient iEEGs. In a first stage, events of interest (EoIs) in the iEEG were defined by thresholds of energy and duration. To recognize HFOs among the EoIs, in a second stage the iEEG was Stockwell-transformed into the time-frequency domain, and the instantaneous power spectrum was parameterized. The parameters were optimized for HFO detection in patient 1 and tested in patients 2–5. Channels were ranked by HFO rate and those with rate above half maximum constituted the HFO area. The seizure onset zone (SOZ) served as gold standard. Results The detector distinguished HFOs from artifacts and other EEG activity such as interictal epileptiform spikes. Computation took few minutes. We found HFOs with relevant power at frequencies also below the 80–500 Hz band, which is conventionally associated with HFOs. The HFO area overlapped with the SOZ with good specificity > 90% for five patients and one patient was re-operated. The performance of the detector was compared to two well-known detectors. Conclusions Compared to methods detecting energy changes in filtered signals, our second stage - analysis in the time-frequency domain - discards spurious detections caused by artifacts or sharp epileptic activity and improves the detection of HFOs. The fast computation and reasonable accuracy hold promise for the diagnostic value of the detector.

Test-retest reliability of EEG spectra during a working memory task

The inter-individual variation of EEG spectra is large even for the same cognitive task. We asked whether task-induced EEG spectra remain stable over more than a year. We recorded EEG in 41 healthy adults who performed a modified Sternberg task. In 20 subjects EEG was recorded in a second session with retest intervals 12-40 months. For electrodes AFz, Cz and Pz peak frequency and peak height were determined. We compared the curve shape of power spectra by regressing spectra pairwise onto each other and calculated a t-value. The t-value and pairwise differences in peak frequency and peak height between all sessions were entered into a generalized linear model (GLM) where binary output represents the recognition probability. The results were cross-validated by out-of-sample testing. Of the 40 sessions, 35 were correctly matched. The shape of power spectra contributed most to recognition. Out of all 2400 pairwise comparisons 99.3% were correct, with sensitivity 87.5% and specificity 99.5%. The intra-individual stability is high compared to the inter-individual variation. Thus, interleaved EEG-fMRI measurements are valid. Furthermore, longitudinal effects on cognitive EEG can be judged against the intra-individual variability in subjects.

Soluble α-klotho: a novel serum biomarker for the activity of GH-producing pituitary adenomas.

OBJECTIVE Klotho is a lifespan-influencing gene expressed mainly in the kidneys. Soluble α-Klotho (αKL) is released into the circulation. In this study, we present baseline αKL serum levels of patients with acromegaly compared with controls with other pituitary adenomas and assess changes following transsphenoidal surgery. DESIGN Prospective controlled study. METHODS We measured soluble αKL (sandwich ELISA) and IGF1 (RIA) in sera of 14 patients (eight females and six males) with active acromegaly and in 22 control patients (13 females and nine males) operated for non-GH-producing pituitary adenomas. Immunohistochemical staining for Klotho was performed in resected adenomas and in normal pituitary tissue samples. RESULTS Soluble αKL was high in the acromegaly group preoperatively (median 4217 pg/ml, interquartile range (IQR) 1812-6623 pg/ml) and declined after surgery during early follow-up (2-6 days; median 645 pg/ml, IQR 550-1303 pg/ml) (P<0.001) and during late follow-up (2-3 months post-operatively; median 902 pg/ml, IQR 497-1340 pg/ml; P<0.001). In controls, preoperative soluble αKL was significantly lower than in acromegalics, 532 pg/ml (400-677 pg/ml; P<0.001). Following surgery, soluble αKL remained low during early and late follow-up - changes over time within the control group were not statistically significant. These results were independent of age, sex and kidney function. Klotho staining was equal or slightly decreased in GH-positive adenomas compared with controls. CONCLUSION High soluble αKL serum levels were specific to GH-producing adenomas and decreased rapidly following adenoma removal. Thus, soluble αKL appears to be a new specific and sensitive biomarker reflecting disease activity in acromegaly. Similar Klotho staining patterns in controls and acromegalics suggest that the rise in serum αKL is caused by systemic actions of pituitary GH rather than due to increased expression of Klotho by the pituitary (adenoma).