Sensory, Motor and Intrinsic Mechanisms of Thalamic Activity related to Organic and Psychogenic Dystonia.

The thalamus is a critical module in the circuit which has been associated with movement disorders including dystonia. This circuit extends from cortex to striatum to pallidum to the thalamic nucleus Ventral Lateral anterior (VLa) to cortex and can be studied by activity recorded during thalamic stereotactic surgery for the treatment of dystonia. Neuronal recordings in the VLa nucleus show low frequency modulation of firing that is correlated with and leads the low frequency modulation of EMG activity; this EMG activity is characteristic of dystonia. Immediately posterior is the Ventral Lateral posterior (VLp) nucleus which, in controls (patients with tremor or chronic pain), is characterized by deep sensory cells which fire at short latency in response to movement of a single joint or to stimulation of deep structures, such as muscles, tendons and joints. In patients with dystonia, neurons with this sensory activity are much more common than in controls and single neurons often respond to movement of multiple joints. In controls operated for the treatment of tremor or chronic pain many neurons in both nuclei are activated during active or involuntary joint movements, such as tremor or dystonia. The active joint movement related to the firing of a cell is usually in the opposite direction to the passive joint movement which causes that cell to fire. This linkage of active or involuntary and passive joint movement is unfocussed in dystonia. The involuntary dystonic joint movement best correlated with firing of a neuron may not activate the neuron when it occurs as a passive movement, while multiple other passive movements will activate the neuron. These linkages may explain the overflow of isolated voluntary activity to multiple other muscles that is seen in dystonia. The activity of either nucleus may have a critical role in dystonia since their disruption by stimulation or lesioning can decrease dystonia.

Oscillatory EEG activity induced by conditioning stimuli during fear conditioning reflects Salience and Valence of these stimuli more than Expectancy.

Imaging studies have described hemodynamic activity during fear conditioning protocols with stimulus trains in which a visual conditioned stimulus (CS+) is paired with an aversive unconditioned stimulus (US, painful laser pulse) while another visual stimulus is unpaired (CS-). We now test the hypothesis that CS Event Related Spectral Perturbations (ERSPs) are related to ratings of CS Expectancy (likelihood of pairing with the US), Valence (unpleasantness) and Salience (ability to capture attention). ERSP windows in EEG were defined by both time after the CS and frequency, and showed increased oscillatory power (Event Related Synchronization, ERS) in the Delta/Theta Windows (0-8Hz) and the Gamma Window (30-55Hz). Decreased oscillatory power (Event Related Desynchronization - ERD) was found in Alpha (8-14Hz) and Beta Windows (14-30Hz). The Delta/Theta ERS showed a differential effect of CS+ versus CS- at Prefrontal, Frontal and Midline Channels, while Alpha and Beta ERD were greater at Parietal and Occipital Channels early in the stimulus train. The Gamma ERS Window increased from habituation to acquisition over a broad area from frontal and occipital electrodes. The CS Valence and Salience were greater for CS+ than CS-, and were correlated with each other and with the ERD at overlapping channels, particularly in the Alpha Window. Expectancy and CS Skin Conductance Response were greater for CS+ than CS- and were correlated with ERSP at fewer channels than Valence or Salience. These results suggest that Alpha ERSP activity during fear conditioning reflects Valence and Salience of the CSs more than conditioning per se.

Vigilance behaviors and EEG activity in sustained attention may affect acute pain.

During Sustained Attention to stimuli across many modalities neural activity often decreases over time on task, while Errors in task performance increase (Vigilance Decrement). Sustained Attention to pain has rarely been investigated experimentally despite its clinical significance. We have employed a Sustained Attention protocol (Continuous Performance Task, CPT) in which the subject counts painful laser stimuli (targets) when they occur randomly in a prolonged train of nonpainful nontargets. We hypothesize that the magnitude of the poststimulus oscillatory power divided by baseline power (Event-Related Spectral Perturbation, ERSP - scalp EEG) over Frontoparietal structures will decrease at all frequencies with time on task, while Beta ERSP (14-30Hz) will be correlated with Error Rates in performance of the CPT. During the CPT with a painful target ERSP was found in four separate Windows, as defined by both their frequency band and the time after the stimulus. A Vigilance Decrement was found which confirms that Sustained Attention to pain was produced by this CPT. In addition, Error Rates was correlated inversely with laser energy, and with ratings of pain unpleasantness and salience. Error Rates also were related directly to the Beta ERSP Window at scalp EEG electrodes over the central sulcus. Over time on task, the ERSP magnitude decreased in Alpha (8-14Hz) Window, was unchanged in early and late Delta/Theta Windows (0-8Hz), and increased in the Beta Window. The increase in Beta ERSP and a decrease in the Alpha ERSP occurred at the same EEG electrode over the parietal lobe to a significant degree across subjects. Overall, Beta activity increases with time on task, and with higher Error Rates as in the case of other modalities. In the case of pain increased Errors correspond to misidentification of painful and nonpainful stimuli and so modulate the sensation of pain under the influence of Sustained Attention.

Functional role of induced gamma oscillatory responses in processing noxious and innocuous sensory events in humans.

Gamma time-frequency responses (TFRs) induced by painful laser in the contralateral primary somatosensory (SI) cortex have been shown to correlate with perceived pain-intensity in human. Given the functional roles of gamma TFRs in the cortical spaces, it remains unclear whether such a relationship is sustained for other brain regions where the laser-evoked potentials (LEPs) are presented. In this study, we delivered the painful laser pluses at random pain-intensity levels (i.e. strong, medium and weak) in a single train to the dorsal hand of six patients with uncontrolled epilepsy. The laser stimulus produced a painful pinprick sensation by activating nociceptors located in the superficial layers of the skin. For each patient, arrays of >64 subdural electrodes were implanted directly covering the contralateral SI, parasylvian (PS) and medial frontal (MF) cortices to study the stimulus related gamma (TFRs) in the neocortex. In addition, using the same stimulation paradigm, the modality specificity of gamma TFRs was further examined by applying innocuous vibrotactile stimuli to the same regions of the dorsal hand in a separated group of five patients. Our results showed that gamma TFRs are not modality specific, but the largest gamma TFRs were consistently found within the SI region and noxious laser elicited significantly stronger gamma TFRs than innocuous nonpainful vibratory stimuli. Furthermore, stronger pain induced stronger gamma TFRs in the cortices of SI (r=0.4, p<0.001) and PS (r=0.29, p=0.005). Given that potentially harmful noxious stimulus would automatically capture greater attention than the innocuous ones, our results support the hypothesis that the degree of SI and PS gamma TFRs is associated with an attentional drive provoked by painful stimuli.

Cross-frequency coupling in deep brain structures upon processing the painful sensory inputs.

Cross-frequency coupling has been shown to be functionally significant in cortical information processing, potentially serving as a mechanism for integrating functionally relevant regions in the brain. In this study, we evaluate the hypothesis that pain-related gamma oscillatory responses are coupled with low-frequency oscillations in the frontal lobe, amygdala and hippocampus, areas known to have roles in pain processing. We delivered painful laser pulses to random locations on the dorsal hand of five patients with uncontrolled epilepsy requiring depth electrode implantation for seizure monitoring. Two blocks of 40 laser stimulations were delivered to each subject and the pain-intensity was controlled at five in a 0-10 scale by adjusting the energy level of the laser pulses. Local-field-potentials (LFPs) were recorded through bilaterally implanted depth electrode contacts to study the oscillatory responses upon processing the painful laser stimulations. Our results show that painful laser stimulations enhanced low-gamma (LH, 40-70 Hz) and high-gamma (HG, 70-110 Hz) oscillatory responses in the amygdala and hippocampal regions on the right hemisphere and these gamma responses were significantly coupled with the phases of theta (4-7 Hz) and alpha (8-1 2 Hz) rhythms during pain processing. Given the roles of these deep brain structures in emotion, these findings suggest that the oscillatory responses in these regions may play a role in integrating the affective component of pain, which may contribute to our understanding of the mechanisms underlying the affective information processing in humans.

The Effect of Walking Speed on Gait Variability in Healthy Young, Middle-aged and Elderly Individuals.

Previous research with healthy young adults has suggested that the temporal structure of gait variability is not random but shows self-similarity that is dependent on speed. Specifically, the strength of the long-range correlation of stride intervals follows a quadratic relationship with the minimum values at the respective preferred walking speed (PWS). The purpose of this study was to investigate if this relationship is affected by increasing age. Ten healthy young, seven healthy, middle-aged and seven healthy, elderly adults completed five-minute walking trials at 80%, 90%, 100%, 110% and 120% of their PWS on a treadmill. We investigated the temporal structure of gait variability by using detrended fluctuation analysis. In addition, we computed the Coefficient of Variation (CV) to identify effects on amount of gait variability. Our results revealed a significant quadratic relationship between the temporal structure of gait variability and speed for all groups extending the previously reported existence of such a relationship in healthy young adults to older individuals. However, only significant negative linear relationships were found between amount of variability and speed providing support that this relationship is not quadratic but linear across individuals of different ages. In addition, we found that the examination of the temporal structure of gait variability is more sensitive in differentiating middle-age and younger individuals. If middle-age is where the aging process starts, then measures of the temporal structure of gait variability are essential as prognostic and diagnostic tools of aging.

Painful cutaneous laser stimuli induce event-related gamma-band activity in the lateral thalamus of humans.

Although the thalamus is an important module in "pain networks," there are few studies of the effect of experimental pain upon thalamic oscillations. We have now examined the hypothesis that, during a series of painful cutaneous laser stimuli, thalamic signals will show stimulus-related gamma-band spectral activity, which is modulated by attention to vs. distraction from the painful stimulus. When the series of laser stimuli was presented, attention was focused by counting the laser stimuli (count laser task), while distraction was produced by counting backward (count back plus laser task). We have studied the effect of a cutaneous laser on thalamic local field potentials and EEG activity during awake procedures (deep brain stimulation implants) for the treatment of essential tremor. At different delays after the stimulus, three low gamma- (30-50 Hz) and two high gamma-band (70-90 Hz) activations were observed during the two tasks. Greater high-gamma activation was found during the count laser task for the earlier window, while greater high-gamma activation was found during the count back plus laser task for the later window. Thalamic signals were coherent with EEG signals in the beta band, which indicated significant synchrony. Thalamic cross-frequency coupling analysis indicated that the phase of the lower frequency activity (theta to beta) modulated the amplitude of the higher frequency activity (low and high gamma) more strongly during the count laser task than during the count back plus laser task. This modulation might result in multiplexed signals each encoding a different aspect of pain.

Painful cutaneous laser stimuli induce event-related oscillatory EEG activities that are different from those induced by nonpainful electrical stimuli.

The non-phase-locked EEG response to painful stimuli has usually been characterized as decreased oscillatory activity (event-related desynchronization, ERD) in the alpha band. Increased activity (event-related synchronization, ERS) in the gamma band has been reported more recently. We have now tested the hypothesis that the non-phase-locked responses to nonpainful electric cutaneous stimuli are different from those to painful cutaneous laser stimuli when the baseline salience of the two stimuli is the same and the salience during the protocol is modulated by count laser and count electric tasks. Both of these stimuli were presented in random order in a single train at intensities that produced the same baseline salience in the same somatic location. The response to the laser stimulus was characterized by five windows (designated windows I-V) in the time-frequency domain: early (200-400 ms) and late (600-1,400 ms) delta/theta ERS, 500-900 ms alpha ERD, 1,200-1,600 ms beta ERS (rebound), and 800-1,200 ms gamma ERS. Similar ERS/ERD windows of activity were found for the electric stimulus. Individual participants very commonly had activity in windows consistent with the overall analysis. Linear regression of ERS/ERD for parietal channels was most commonly found for sensory (pain or unpleasantness)- or attention (salience)-related measures. Overall, the main effect for modality was found in window I-delta/theta and window V-gamma, and the Modality with Task interaction was found in all five windows. All significant interaction terms included Modality as a factor. Therefore, Modality was the most common factor explaining our results, which is consistent with our hypothesis.

EEG analysis reveals widespread directed functional interactions related to a painful cutaneous laser stimulus.

During attention to a painful cutaneous laser stimulus, event-related causality (ERC) has been detected in recordings from subdural electrodes implanted directly over cortical modules for the treatment of epilepsy. However, these studies afforded limited sampling of modules and did not examine interactions with a nonpainful stimulus as a control. We now sample scalp EEG to test the hypothesis that attention to the laser stimulus is associated with poststimulus ERC interactions that are different from those with attention to a nonpainful stimulus. Subjects attended to (counted) either a painful laser stimulus (laser attention task) or a nonpainful electrical cutaneous stimulus that produced distraction from the laser (laser distraction task). Both of these stimuli were presented in random order in a single train. The intensities of both stimuli were adjusted to produce similar baseline salience and sensations in the same cutaneous territory. The results demonstrated that EEG channels with poststimulus ERC interactions were consistently different during the laser stimulus versus the electric stimulus. Poststimulus ERC interactions for the laser attention task were different from the laser distraction task. Furthermore, scalp EEG frontal channels play a driver role while parietal temporal channels play a receiver role during both tasks, although this does not prove that these channels are connected. Sites at which large numbers of ERC interactions were found for both laser attention and distraction tasks (critical sites) were located at Cz, Pz, and C3. Stimulation leading to disruption of sites of these pain-related interactions may produce analgesia for acute pain.

Assessment of a scalp EEG-based automated seizure detection system.

OBJECTIVE: The purpose of this study was to evaluate and validate an offline, automated scalp EEG-based seizure detection system and to compare its performance to commercially available seizure detection software. METHODS: The test seizure detection system, IdentEvent™, was developed to enhance the efficiency of post-hoc long-term EEG review in epilepsy monitoring units. It translates multi-channel scalp EEG signals into multiple EEG descriptors and recognizes ictal EEG patterns. Detection criteria and thresholds were optimized in 47 long-term scalp EEG recordings selected for training (47 subjects, ∼3653h with 141 seizures). The detection performance of IdentEvent was evaluated using a separate test dataset consisting of 436 EEG segments obtained from 55 subjects (∼1200h with 146 seizures). Each of the test EEG segments was reviewed by three independent epileptologists and the presence or absence of seizures in each epoch was determined by majority rule. Seizure detection sensitivity and false detection rate were calculated for IdentEvent as well as for the comparable detection software (Persyst's Reveal®, version 2008.03.13, with three parameter settings). Bootstrap re-sampling was applied to establish the 95% confidence intervals of the estimates and for the performance comparison between two detection algorithms. RESULTS: The overall detection sensitivity of IdentEvent was 79.5% with a false detection rate (FDR) of 2 per 24h, whereas the comparison system had 80.8%, 76%, and 74% sensitivity using its three detection thresholds (perception score) with FDRs of 13, 8, and 6 per 24h, respectively. Bootstrap 95% confidence intervals of the performance difference revealed that the two detection systems had comparable detection sensitivity, but IdentEvent generated a significantly (p<0.05) smaller FDR. CONCLUSIONS: The study validates the performance of the IdentEvent™ seizure detection system. SIGNIFICANCE: With comparable detection sensitivity, an improved false detection rate makes the automated seizure detection software more useful in clinical practice.

WITHDRAWN: A radio frequency biosensor with gold nanoparticle probes.

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