What does the broken brain say to the neuroscientist? Oscillations and connectivity in schizophrenia, Alzheimer's disease, and bipolar disorder.

The application of the concept and methods of brain oscillations has been an important research area in neurosciences. In the last decades, besides the application in cognitive processes, the study of changes in brain oscillations in diseases has also become an important focal point of research. In the present paper, some remarkable examples in three different diseases are taken into consideration: 1) schizophrenia (SZ), 2) Alzheimer's disease (AD), 3) bipolar disorders (BD). In the current literature, decreased oscillations in cortical recordings are observed in most of the pathologies. For example, decrease of gamma activity in SZ, decrease of delta activity in almost all diseases, as well as frequency shifts in alpha and the lower frequencies were recorded. However, there are also paradoxical cases in which an increase of oscillatory activities is observed. In BD, whereas alpha activity is greatly decreased, a huge increase of beta activity is observed. Or, in SZ, a paradoxical increase of gamma activity can be observed during cognitive loading. We also observed paradoxical changes in the analysis of connectivity. In AD, we find that alpha, delta, and theta coherences between distant parts of the cortex are greatly decreased, whereas in the gamma band, event-related coherences attain very high values. The comparison of the results and paradoxical changes in diseases may lead to important conclusions related to the web of oscillations and neurotransmitters. In turn, we could gain new insights to approach "brain function", in general.

Decrease of theta response in euthymic bipolar patients during an oddball paradigm.

Theta oscillations are related to cognitive functions and reflect functional integration of frontal and medial temporal structures into coherent neurocognitive networks. This study assessed event-related theta oscillations in medication-free, euthymic patients with bipolar disorder upon auditory oddball paradigm. Twenty-two DSM-IV euthymic bipolar I (n = 19) and II (n = 3) patients and twenty-two healthy subjects were included. Patients were euthymic for at least 6 months, and psychotropic-free for at least 2 weeks. EEG was recorded at 30 electrode sites. Auditory oddball paradigm and sensory stimuli were used. Event-related Oscillations were analyzed using adaptive filtering in two different theta frequency bands (4-6 Hz, 6-8 Hz). In healthy subjects, slow theta (4-6 Hz) responses were significantly higher than those of euthymic patients upon target, non-target and sensory stimuli (p < 0.05). Fast theta (6-8 Hz) responses of healthy subjects were significantly higher than those of euthymic patients upon target-only stimuli (p < 0.05). Reduced theta oscillations during auditory processing provide strong quantitative evidence of activation deficits in related networks in bipolar disorder. Fast theta responses are related to cognitive functions, whereas slow theta responses are related to sensory processes more than cognitive processes.

Brain's alpha activity is highly reduced in euthymic bipolar disorder patients.

Brain's alpha activity and alpha responses belong to major electrical signals that are related to sensory/cognitive signal processing. The present study aims to analyze the spontaneous alpha activity and visual evoked alpha response in drug free euthymic bipolar patients. Eighteen DSM-IV euthymic bipolar patients (bipolar I n = 15, bipolar II n = 3) and 18 healthy controls were enrolled in the study. Patients needed to be euthymic at least for 4 weeks and psychotrop free for at least 2 weeks. Spontaneous EEG (4 min eyes closed, 4 min eyes open) and evoked alpha response upon application of simple visual stimuli were analyzed. EEG was recorded at 30 positions. The digital FFT-based power spectrum analysis was performed for spontaneous eyes closed and eyes open conditions and the response power spectrum was also analyzed for simple visual stimuli. In the analysis of spontaneous EEG, the ANOVA on alpha responses revealed significant results for groups (F(1,34) = 8.703; P < 0.007). Post-hoc comparisons showed that spontaneous EEG alpha power of healthy subjects was significantly higher than the spontaneous EEG alpha power of euthymic patients. Furthermore, visual evoked alpha power of healthy subjects was significantly higher than visual evoked alpha power of euthymic patients (F(1,34) = 4.981; P < 0.04). Decreased alpha activity in spontaneous EEG is an important pathological EEG finding in euthymic bipolar patients. Together with an evident decrease in evoked alpha responses, the findings may lead to a new pathway in search of biological correlates of cognitive impairment in bipolar disorder.

Auditory delta event-related oscillatory responses are decreased in Alzheimer's disease.

BACKGROUND: Visual delta event-related (ERO) and evoked oscillations (EO) of Alzheimer patients (AD) are different than healthy. In the present study, the analysis is extented to include auditory ERO and EO in AD. The rationale is to reveal whether the auditory ERO delta responses are also reduced, and whether this is a general phenomenon in Alzheimer patients upon applying stimuli with cognitive load. METHODS: Thirty-four mild AD subjects [17 de-novo and 17 medicated (cholinergic)] and seventeen healthy controls were included. Auditory oddball paradigm and sensory auditory stimuli were applied to the subjects. Oscillatory responses were analyzed by measuring maximum amplitudes in delta frequency range (0.5-3.5 Hz). RESULTS: Auditory delta ERO (0.5-3.5 Hz) responses of healthy controls were higher than either de-novo AD or medicated AD group, without a difference between two AD subgroups. Furthermore, the auditory EO after presentation of tone bursts yielded no group difference. CONCLUSION: Our findings imply that delta ERO is highly unstable in AD patients in comparison to age-matched healthy controls only during the cognitive paradigm. Our results favor the hypothesis that neural delta networks are activated during cognitive tasks and that the reduced delta response is a general phenomenon in AD, due to cognitive impairment.

Event-related delta oscillatory responses of Alzheimer patients.

BACKGROUND AND PURPOSE: Alzheimer type of dementia (AD) is the most common neuropsychiatric morbidity in elderly individuals. Event-related oscillations (ERO) provide an useful tool for detecting subtle abnormalities of cognitive processes with high temporal resolution. METHODS: In the present report, event-related oscillations of patients with AD were analyzed by using a visual oddball paradigm. A total of 22 mild probable AD subjects according to NINCDS-ADRDA criteria and 20 age-, gender-, and education-matched healthy control subjects were compared. AD group consisted from 11 untreated patients and 11 patients treated with cholinesterase inhibitor. Oscillatory responses were recorded from 13 scalp electrodes. RESULTS: Significant differences in delta frequency range were seen between the groups by using repeated measures of anova analysis [F(9.120) = 2.228; P = 0.022]. Post-hoc analyses using Wilcoxon test showed that at mid- and left central regions, (Cz, C3) peak amplitudes of delta responses of healthy subjects were significantly higher than either group. Also cholinesterase inhibitors did not have effect on delta oscillatory responses. CONCLUSIONS: Our findings imply that the delta oscillatory responses at central locations are highly instable in mild probable AD patients regardless of treatment when compared to the healthy aged controls. This study supports the importance of oscillatory event-related potentials for investigating AD brain dynamics.

Increased frontal phase-locking of event-related theta oscillations in Alzheimer patients treated with cholinesterase inhibitors.

This is a pilot study describing event-related oscillations in patients with Alzheimer-type dementia (AD). Theta responses of 22 mild probable AD subjects according to NINCDS-ADRDA criteria (11 non-treated, 11 treated by cholinesterase inhibitors), and 20 healthy elderly controls were analyzed by using the conventional visual oddball paradigm. We aimed to compare theta responses of the three groups in a range between 4-7 Hz at the frontal electrodes. At F(3) location, theta responses of healthy subjects were phase locked to stimulation and theta oscillatory responses of non-treated Alzheimer patients showed weaker phase-locking, i.e. average of Z-transformed means of correlation coefficients between single trials was closer to zero. In treated AD patients, phase-locking following target stimulation was two times higher in comparison to the responses of non-treated patients. The results indicate that the phase-locking of theta oscillations at F(3) in the treated patients is as strong as the control subjects. The F(4) theta responses were not statistically significant between the groups. Our findings imply that the theta responses at F(3) location are highly unstable in comparison to F(4) in non-treated mild AD patients and cholinergic agents may modulate event-related theta oscillatory activities in the frontal regions.

Wavelet Transform in the analysis of the frequency composition of evoked potentials.

This technical paper deals with the application of the Wavelet Transform to the study of evoked potentials. In particular, Wavelet Transform gives an optimal time-dependent frequency decomposition of the evoked responses, something difficult to be achieved with previous methods such as the Fourier Transform. We describe in detail the protocol for implementing the decomposition based on the Wavelet Transform and apply it to two different types of evoked potentials. In the first case we study alpha responses in pattern visual evoked potentials and in the second case, we study gamma responses to bimodal (auditory and visual) stimulation. Although in this study we focus on methodological issues, we briefly discuss physiological implications of the present time-frequency analysis. Furthermore, we show examples of the better performance of the wavelet decomposition in comparison with Fourier-based methods.

The treatment of severe trachomatous dry eye with canalicular silicone plugs.

PURPOSE: To evaluate the effects of temporary canalicular occlusion with silicone plugs on trachomatous dry eye patients who were on maximal tolerable medical therapy. METHODS: Forty-four trachomatous dry eye patients who had Schirmer testing with topical anaesthetic measuring 5 mm or less and a tear film break-up time of 5 s or less were included. After the lacrimal efficiency test with dissolvable collagen punctal plugs, silicone canalicular plugs were placed in 22 trachomatous dry eye patients. The other 22 patients in the untreated control group were allowed to continue their medical therapy. Pretreatment and post-treatment evaluations included subjective patient assessment, rose Bengal and fluorescein staining, tear film break-up time, Schirmer testing, conjunctival impression cytology and goblet cell counting. RESULTS: Six months after plug placement, 18 eyes (82%) of 22 patients had subjective improvement and all these patients successfully wore plugs for at least 6 months. There were statistically significant differences between the pretreatment and post-treatment test results including rose Bengal and fluorescein staining scores, tear film break-up times and Schirmer testing measurements. Impression cytology showed improvement of squamous metaplasia in 17 eyes (77%). Eight of the patients (36%) were able to decrease dependency on topical therapy. Ten of the patients (45%) completely stopped using artificial tears. There were statistically significant differences between the two groups in the total symptom scores, staining scores, tear film break-up time, Schirmer testing, impression cytology scores and goblet cell counts. CONCLUSION: In cases where topical tear supplementation is insufficient to relieve the signs and symptoms of severe dry eye and the lacrimal puncta have not already been closed by the trachomatous cicatrising process, occlusion of the canaliculi may be useful to prevent drainage of both natural and artificial tears. Canalicular occlusion improves the objective signs and subjective symptoms and may significantly decrease dependency on tear supplements in selected patients.

Wavelet entropy in event-related potentials: a new method shows ordering of EEG oscillations.

In this work we show the application of a measure of entropy defined from the wavelet transform, namely the wavelet entropy (WS), to the study of event-related potentials (ERPs). WS was computed for ERPs recorded from nine healthy subjects with three different types of stimuli, among them target stimuli in a cognitive task. A significant decrease of entropy was correlated with the responses to target stimuli (P300), thus showing that these responses correspond to a more "ordered" state than the spontaneous EEG. Furthermore, we propose the WS as a quantitative measure for such transitions between EEG ("disordered state") and ERP ("ordered state").

Bisensory stimulation increases gamma-responses over multiple cortical regions.

In the framework of the discussion about gamma (approx. 40 Hz) oscillations as information carriers in the brain, we investigated the relationship between gamma responses in the EEG and intersensory association. Auditory evoked potentials (AEPs) and visual evoked potentials (VEPs) were compared with bisensory evoked potentials (BEPs; simultaneous auditory and visual stimulation) in 15 subjects. Gamma responses in AEPs, VEPs and BEPs were assessed by means of wavelet decomposition. Overall maximum gamma-components post-stimulus were highest in BEPs (P < 0.01). Bisensory evoked gamma-responses also showed significant central, parietal and occipital amplitude-increases (P < 0.001, P < 0.01, P < 0.05, respectively; prestimulus interval as baseline). These were of greater magnitude when compared with the unisensory responses. As a correlate of the marked gamma responses to bimodal stimulation we suggest a process of 'intersensory association', i.e. one of the steps between sensory transmission and perception. Our data may be interpreted as a further example of function-related gamma responses in the EEG.

Event-related oscillations are 'real brain responses'--wavelet analysis and new strategies.

The EEG consists of the activity of an ensemble of generators producing rhythmic activity in several frequency ranges. These oscillators are active usually in a random way. However, by application of sensory stimulation these generators are coupled and act together in a coherent way. This synchronization and enhancement of EEG activity gives rise to 'evoked' or 'event-related oscillations'. The compound evoked potential manifests as superimposition of evoked rhythms in the EEG frequencies ranging from delta to gamma ('natural frequencies of the brain'). The superimposition principle is described with efficient strategies and by utilization of an efficient algorithm. The wavelet analysis confirms the results of the combined analysis procedure obtained by using the amplitude frequency characteristics (AFCs) and digital filtering. The AFC and adapted digital filtering methods are based on the first approach to analyze average evoked potentials. In contrast, the wavelet analysis is based on signal retrieval and selection among a large number of sweeps recorded in a given physiological or psychological experiment. By combining all these results and concepts, it can be stated that the wavelet analysis underlines and extends the expression that alpha-, theta-, delta-, and gamma-responses described in this report are the most important brain responses related to psychophysiological functions. The wavelet analysis confirms once more the expression 'real signals' which we attribute to EEG frequency responses of the brain. It will be demonstrated that the delta, theta, and alpha responses (i.e. the rhythms 'predicted' by digital filtering) are real brain oscillations. The frequency components of the event-related potential vary independently of each other with respect to: (a) their relation to the event; (b) their topographic distribution; and (c) with the mode of the physiological measurements.

Selectively distributed gamma band system of the brain.

Experiments from the cat brain demonstrate that gamma responses can be recorded in cortex, hippocampus, cerebellum, formatio reticularis and thalamus, independent of the mode of sensory stimulation. These results support the hypothesis of a selectively distributed gamma system of the brain.

Functional aspects of alpha oscillations in the EEG.

Experimental evidence suggests a functional significance of EEG alpha rhythms. Event-related, evoked, and induced alpha rhythms may have functional correlates in primary sensory processing and preparatory processes. These results are in accordance with the view that spontaneous and induced EEG alpha rhythms have quasi-deterministic properties.

Increased frontal phase-locking of event-related alpha oscillations during task processing.

Recent findings substantiate the view that electroencephalographic (EEG) alpha rhythm (7-13 Hz) is functionally involved in cognitive stimulus processing. Our previous results have shown that enhanced alpha responses to auditory task stimuli can be well synchronized with stimulus until 800-1000 ms. The present study analyzed the effect of perceptual uncertainty and difficulty in decision making on event-related alpha oscillations in single auditory event-related brain potentials (ERPs). EEG was recorded from Fz, Cz and Pz electrodes in 10 subjects participating in two experimental sessions, in which auditory stimuli with equal physical parameters were presented under passive and task instructions. Separate measurements of single alpha response amplitude and phase-locking were performed and statistically analyzed for consecutive time windows in the post-stimulus epoch. Major results show that, during the cognitive task, the phase-locking of alpha oscillations at the frontal site is significantly increased in the time window of 500-1000 ms after stimulation. Thus, the involvement of enhanced and synchronized frontal alpha activity in higher brain processes is strongly emphasized.

The selectively distributed theta system: functions.

The present paper provides three interwoven or interrelated approaches: (1) the dependence of frontal theta response from the spontaneous activity will be pointed out. This helps in understanding that 'frontal theta' is a major oscillation of the human frontal cortex and has a response-controlling function; (2) it will be shown that complex stimulations such as bimodal stimulation enhances the theta response; and by bringing together the results outlined in a number of previous reviews the so-called 'selectively distributed theta system of the brain' is described.

Topological distribution of oddball 'P300' responses.

This report describes the frequency response of the oddball paradigm upon auditory stimuli. Other reports related to wavelet analysis of the same ERPs (Demiralp et al., 1999) and the application of visual signals (Schürmann et al., this volume) indicate that the P300 response has a dominant delta response oscillation, independent of the modality of the stimulation. Moreover, the adaptive digital filtering and the wavelet analysis lead to very similar results, confirming that delta responses are real brain responses as already mentioned, by Basar et al. (this volume). The theta response has a second late response window in comparison to auditory evoked potentials. Moreover, the functional significance of the selectively distributed theta and delta systems of the brain will be clearly demonstrated. Signal detection, short-term memory, and decision-making processes are discussed.

Wavelet analysis of oddball P300.

The comparative wavelet analysis presented in details by Demiralp et al. (1999), Ademoglu (1995) and by Basar et al. (2001) will be now applied to oddball P300 results (see Basar-Eroglu et al., 2001). The results obtained basically confirm those obtained by using adaptive digital filtering: The delta response dominates the P300 potential while the theta response is prolonged in a second late window.

Delta responses and cognitive processing: single-trial evaluations of human visual P300.

Visual P300 responses were recorded by using checkerboard-type stimuli. (1) High amplitude P300-delta responses were visible even in single trial ERPs. (2) An algorithm for efficient selection of P300 single trials (based on evaluation of delta responses) is introduced. (3) The 'universal' character of the P300-delta response demonstrated in this report may open new avenues for the understanding of functional ERP components.

Gamma, alpha, delta, and theta oscillations govern cognitive processes.

The increased interest in gamma oscillations, now widely regarded as functionally relevant signals of the brain, underlines the importance of the concept of event-related oscillations for bridging the gap between single neurons and neural assemblies. Taking this concept further, we review experiments showing that oscillatory phenomena such as alpha, theta, and delta responses to events are, just as the gamma band, strongly interwoven with sensory and cognitive functions. This review argues that selectively distributed delta, theta, alpha and gamma oscillatory systems act as resonant communication networks through large populations of neurons. Thus, oscillatory processes might play a major role in functional communication in the brain in relation to memory and integrative functions.