Aspect-Oriented Programming enables developers to capture in separated aspect modules concerns th... more Aspect-Oriented Programming enables developers to capture in separated aspect modules concerns that are spread over different components in a system. This paper is an attempt to apply this paradigm to High Performance Computing. Besides achieving the usual advantages of improved modularity, more reusable code that is easier to develop and maintain, we pursue to improve efficiency by means of dynamic changes of aspects at runtime.
Objectives To compare the effects of typical and atypical antipsychotic drugs on sleep activity a... more Objectives To compare the effects of typical and atypical antipsychotic drugs on sleep activity and subjective sleep quality. Design Randomised, double-blind, placebo-controlled, four-period cross-over, clinical trial was used to evaluate the effects of active treatments on objective and subjective sleep variables. Setting Sleep laboratory evaluation. Participants Twenty healthy young volunteers, both sexes. Interventions Single oral morning administrations of olanzapine 5 mg, risperidone 1 mg, haloperidol 3 mg and placebo. Measurements and results Five polysomnographic nights were evaluated: one control night and one after each intervention. Significant increase in total sleep time, sleep efficiency, slow wave sleep (SWS) and rapid eye movement (REM) sleep with decreases in wake time were observed after olanzapine. Decreases in wake time, REM sleep and stage shifts together with increases in stage 2 were obtained after risperidone. Haloperidol showed only a tendency to increase sleep efficiency and stage 2 and to decrease wake time. Olanzapine showed decreases in power density in frequencies higher than 10 Hz during all sleep stages and in frequencies lower than 5 Hz range in SWS; decreases in the dynamics of spindle frequency activity (SFA) in the second and fourth non-rapid eye movement (NREM) episodes were also obtained. Risperidone presented increases in the 3.6–10.8 Hz frequency range in NREM sleep stages and in stage 2. Haloperidol also showed increases in NREM sleep stages and in stage 2, but these were in frequencies higher than 10 Hz, with increases in the dynamics of SFA in the first NREM episode. Only a significant improvement in subjective sleep quality was observed after olanzapine. Conclusions Antipsychotics showed different sleep changes as their neurochemical profiles were distinct. These changes were observed even when the drug was administered 15 h before going to bed.
Sleep Laboratory Study on Single and Repeated Dose Effects of Paroxetine, Alprazolam and Their Combination in Healthy Young Volunteers
Neuropsychobiology, 2005
To evaluate the potential interaction of 20 mg paroxetine and 1 mg alprazolam (early morning once... more To evaluate the potential interaction of 20 mg paroxetine and 1 mg alprazolam (early morning once-daily administration) on polysomnographic (PSG) sleep and subjective sleep and awakening quality, both after a single intake and after reaching a steady-state concentration. Twenty-two (11 for the PSG) healthy young volunteers of both sexes with no history of sleep disturbances (Pittsburgh Sleep Quality Index <5) participated in a double-blind, double-dummy, placebo-controlled, repeated-dose, 4-period, cross-over study. All volunteers received all 4 treatment sequences: paroxetine-alprazolam placebo (PAP); paroxetine placebo-alprazolam (PPA); paroxetine-alprazolam (PA), and paroxetine placebo-alprazolam placebo (PLA), in a randomized order. Each treatment was administered over 15 consecutive days, with a treatment-free interval of 7 days prior to the subsequent study period. In each experimental period, one PSG sleep study was performed on the 1st night (single-dose effects) and another study was performed on the 15th night (repeated-dose effects). Additionally, two other PSG studies were assessed: an adaptation recording, and a control night recording. All-night PSG recordings were obtained following standard procedures. Each 30-second period was scored according to the criteria of Rechtschaffen and Kales by means of an automatic sleep analysis system: Somnolyzer 24x7. A self-rating scale for sleep and awakening quality and early morning behavior was completed no later than 15 min after awakening over the 15 days of each experimental intervention. General lineal models (treatment/time) were applied separately to each variable. (1) No significant effects were observed in any sleep variables when control nights were compared with the 1st night with PLA. (2) Sleep continuity: After PAP a clear awakening effect was seen both in the first and second evaluations, mainly in wake time, movement time, number of awakenings and stage-1 duration. After PPA an evident hypnotic effect was observed on night 1. This effect was mainly observed in maintenance variables and slightly in sleep initiation variables; it had decreased by night 15. After PA an intermediate behavior in the variables related to sleep continuity was seen, highlighting the absence of the tolerance phenomenon observed when PPA was administered alone. (3) Sleep architecture: The most important effects in REM sleep were observed after PAP; an increase in REM latency and decreases in REM sleep. PAP also induced decreases in the number of non-REM and REM periods and increases in the average duration of non-REM periods and sleep cycles. PA presented a similar pattern to PAP, and PPA similar to PLA. In relation to non-REM sleep, PA showed more stage-2 and less slow-wave sleep (SWS). (4) Subjective perception: No significant differences were observed between treatments while they were being taken, but impairments in subjective sleep quality, awaking quality, latency and efficiency were seen, mainly after PA but also after PPA discontinuations. The combination of PAP and PPA presented an intermediate pattern in relation to sleep continuity, with less awaking effect than PAP alone and less hypnotic effect than PPA alone, and without developing tolerance. The PAP and PPA combination also showed a similar effect to PAP on REM sleep and was the treatment with the longest stage 2 and shortest SWS. No subjective sleep and awakening effects were seen during drug intake but subjective withdrawal reports were seen after abrupt interruption. The high agreement rate for the epoch-by-epoch comparison between automatic and human scoring confirms the validity of the Somnolyzer 24x7 and thus facilitates sleep studies in neuropsychopharmacological research.
Quantitative electroencephalographic (EEG) analysis is very useful for diagnosing dysfunctional n... more Quantitative electroencephalographic (EEG) analysis is very useful for diagnosing dysfunctional neural states and for evaluating drug effects on the brain, among others. However, the bidirectional contamination between electrooculographic (EOG) and cerebral activities can mislead and induce wrong conclusions from EEG recordings. Different methods for ocular reduction have been developed but only few studies have shown an objective evaluation of their performance. For this purpose, the following approaches were evaluated with simulated data: regression analysis, adaptive filtering, and blind source separation (BSS). In the first two, filtered versions were also taken into account by filtering EOG references in order to reduce the cancellation of cerebral high frequency components in EEG data. Performance of these methods was quantitatively evaluated by level of similarity, agreement and errors in spectral variables both between sources and corrected EEG recordings. Topographic distributions showed that errors were located at anterior sites and especially in frontopolar and lateral–frontal regions. In addition, these errors were higher in theta and especially delta band. In general, filtered versions of time-domain regression and of adaptive filtering with RLS algorithm provided a very effective ocular reduction. However, BSS based on second order statistics showed the highest similarity indexes and the lowest errors in spectral variables.
Eye movement artifacts represent a critical issue for quantitative electroencephalography (EEG) a... more Eye movement artifacts represent a critical issue for quantitative electroencephalography (EEG) analysis and a number of mathematical approaches have been proposed to reduce their contribution in EEG recordings. The aim of this paper was to objectively and quantitatively evaluate the performance of ocular filtering methods with respect to spectral target variables widely used in clinical and functional EEG studies. In particular the following methods were applied: regression analysis and some blind source separation (BSS) techniques based on second-order statistics (PCA, AMUSE and SOBI) and on higher-order statistics (JADE, INFOMAX and FASTICA). Considering blind source decomposition methods, a completely automatic procedure of BSS based on logical rules related to spectral and topographical information was proposed in order to identify the components related to ocular interference. The automatic procedure was applied in different montages of simulated EEG and electrooculography (EOG) recordings: a full montage with 19 EEG and 2 EOG channels, a reduced one with only 6 EEG leads and a third one where EOG channels were not available. Time and frequency results in all of them indicated that AMUSE and SOBI algorithms preserved and recovered more brain activity than the other methods mainly at anterior regions. In the case of full montage: (i) errors were lower than 5% for all spectral variables at anterior sites; and (ii) the highest improvement in the signal-to-artifact (SAR) ratio was obtained up to 40 dB at these anterior sites. Finally, we concluded that second-order BSS-based algorithms (AMUSE and SOBI) provided an effective technique for eye movement removal even when EOG recordings were not available or when data length was short. ᭧
Evaluation of an automatic ocular filtering method for awake spontaneous EEG signals based on independent component analysis
Electroencephalographic artifacts associated with eye movements are a potential source of error i... more Electroencephalographic artifacts associated with eye movements are a potential source of error in the EEG analysis when its interpretation is performed for evaluating the influence of drugs and the diagnosis of neurological disorders. In this study, a new automatic method for artifact filtering based on independent component analysis (ICA) is proposed. Automatic artifact identification is based on frequency domain and scalp topography aspects of the independent components. A comparative study between ICA and the 'gold standard' method based on linear regression analysis is performed. The latter does not take into account the mutual contamination between EEG and electrooculographic activity, reducing not only the ocular movements but also interesting cerebral activity, mainly in anteriorly placed electrodes. This limitation is overcome by ICA and the efficiency of this approach is shown for a double-blind, placebo-controlled crossover drug trial in healthy volunteers.
Reduction of EEG artifacts by ICA in different sleep stages
Contamination of sleep EEG signals by the eye, muscle and heart activity is a problem for EEG int... more Contamination of sleep EEG signals by the eye, muscle and heart activity is a problem for EEG interpretation and analysis of sleep disorders and influence of drugs. The aim of this paper is to evaluate a method of artifact reduction applied in different sleep stages: awakeness, stage 2, delta and REM sleep. Artifacts, particularly certain types, may be more likely found in particular settings and stages of sleep. To overcome the limitation of regression methods in bidirectional contamination, a method based on Independent Component Analysis (ICA) using time structure is applied. Artifact identification is based on time, frequency and scalp topography aspects of the independent components. Influence of artifacts is evaluated by calculating some target spectral variables before and after their reduction, using significance probability maps. Results show that ICA is a useful technique for the evaluation of these variables with clinical interest in different sleep stages.
Rationale Ayahuasca is a South American psychoactive plant tea which contains the serotonergic ps... more Rationale Ayahuasca is a South American psychoactive plant tea which contains the serotonergic psychedelic N,N-dimethyltryptamine (DMT) and monoamine-oxidase inhibitors that render DMT orally active. Previous investigations with ayahuasca have highlighted a psychotropic effect profile characterized by enhanced introspective attention, with individuals reporting altered somatic perceptions and intense emotional modifications, frequently accompanied by visual imagery. Despite recent advances in the study of ayahuasca pharmacology, the neural correlates of acute ayahuasca intoxication remain largely unknown. Objectives To investigate the effects of ayahuasca administration on regional cerebral blood flow. Methods Fifteen male volunteers with prior experience in the use of psychedelics received a single oral dose of encapsulated freeze-dried ayahuasca equivalent to 1.0 mg DMT/kg body weight and a placebo in a randomized double-blind clinical trial. Regional cerebral blood flow was measured 100–110 min after drug administration by means of single photon emission tomography (SPECT). Results Ayahuasca administration led to significant activation of frontal and paralimbic brain regions. Increased blood perfusion was observed bilaterally in the anterior insula, with greater intensity in the right hemisphere, and in the anterior cingulate/frontomedial cortex of the right hemisphere, areas previously implicated in somatic awareness, subjective feeling states, and emotional arousal. Additional increases were observed in the left amygdala/parahippocampal gyrus, a structure also involved in emotional arousal. Conclusions The present results suggest that ayahuasca interacts with neural systems that are central to interoception and emotional processing and point to a modulatory role of serotonergic neurotransmission in these processes.
Objectives To compare the effects of typical and atypical antipsychotic drugs on sleep activity a... more Objectives To compare the effects of typical and atypical antipsychotic drugs on sleep activity and subjective sleep quality. Design Randomised, double-blind, placebo-controlled, four-period cross-over, clinical trial was used to evaluate the effects of active treatments on objective and subjective sleep variables. Setting Sleep laboratory evaluation. Participants Twenty healthy young volunteers, both sexes. Interventions Single oral morning administrations of olanzapine 5 mg, risperidone 1 mg, haloperidol 3 mg and placebo. Measurements and results Five polysomnographic nights were evaluated: one control night and one after each intervention. Significant increase in total sleep time, sleep efficiency, slow wave sleep (SWS) and rapid eye movement (REM) sleep with decreases in wake time were observed after olanzapine. Decreases in wake time, REM sleep and stage shifts together with increases in stage 2 were obtained after risperidone. Haloperidol showed only a tendency to increase sleep efficiency and stage 2 and to decrease wake time. Olanzapine showed decreases in power density in frequencies higher than 10 Hz during all sleep stages and in frequencies lower than 5 Hz range in SWS; decreases in the dynamics of spindle frequency activity (SFA) in the second and fourth non-rapid eye movement (NREM) episodes were also obtained. Risperidone presented increases in the 3.6–10.8 Hz frequency range in NREM sleep stages and in stage 2. Haloperidol also showed increases in NREM sleep stages and in stage 2, but these were in frequencies higher than 10 Hz, with increases in the dynamics of SFA in the first NREM episode. Only a significant improvement in subjective sleep quality was observed after olanzapine. Conclusions Antipsychotics showed different sleep changes as their neurochemical profiles were distinct. These changes were observed even when the drug was administered 15 h before going to bed.
Sleep Laboratory Study on Single and Repeated Dose Effects of Paroxetine, Alprazolam and Their Combination in Healthy Young Volunteers
Neuropsychobiology, 2005
To evaluate the potential interaction of 20 mg paroxetine and 1 mg alprazolam (early morning once... more To evaluate the potential interaction of 20 mg paroxetine and 1 mg alprazolam (early morning once-daily administration) on polysomnographic (PSG) sleep and subjective sleep and awakening quality, both after a single intake and after reaching a steady-state concentration. Twenty-two (11 for the PSG) healthy young volunteers of both sexes with no history of sleep disturbances (Pittsburgh Sleep Quality Index <5) participated in a double-blind, double-dummy, placebo-controlled, repeated-dose, 4-period, cross-over study. All volunteers received all 4 treatment sequences: paroxetine-alprazolam placebo (PAP); paroxetine placebo-alprazolam (PPA); paroxetine-alprazolam (PA), and paroxetine placebo-alprazolam placebo (PLA), in a randomized order. Each treatment was administered over 15 consecutive days, with a treatment-free interval of 7 days prior to the subsequent study period. In each experimental period, one PSG sleep study was performed on the 1st night (single-dose effects) and another study was performed on the 15th night (repeated-dose effects). Additionally, two other PSG studies were assessed: an adaptation recording, and a control night recording. All-night PSG recordings were obtained following standard procedures. Each 30-second period was scored according to the criteria of Rechtschaffen and Kales by means of an automatic sleep analysis system: Somnolyzer 24x7. A self-rating scale for sleep and awakening quality and early morning behavior was completed no later than 15 min after awakening over the 15 days of each experimental intervention. General lineal models (treatment/time) were applied separately to each variable. (1) No significant effects were observed in any sleep variables when control nights were compared with the 1st night with PLA. (2) Sleep continuity: After PAP a clear awakening effect was seen both in the first and second evaluations, mainly in wake time, movement time, number of awakenings and stage-1 duration. After PPA an evident hypnotic effect was observed on night 1. This effect was mainly observed in maintenance variables and slightly in sleep initiation variables; it had decreased by night 15. After PA an intermediate behavior in the variables related to sleep continuity was seen, highlighting the absence of the tolerance phenomenon observed when PPA was administered alone. (3) Sleep architecture: The most important effects in REM sleep were observed after PAP; an increase in REM latency and decreases in REM sleep. PAP also induced decreases in the number of non-REM and REM periods and increases in the average duration of non-REM periods and sleep cycles. PA presented a similar pattern to PAP, and PPA similar to PLA. In relation to non-REM sleep, PA showed more stage-2 and less slow-wave sleep (SWS). (4) Subjective perception: No significant differences were observed between treatments while they were being taken, but impairments in subjective sleep quality, awaking quality, latency and efficiency were seen, mainly after PA but also after PPA discontinuations. The combination of PAP and PPA presented an intermediate pattern in relation to sleep continuity, with less awaking effect than PAP alone and less hypnotic effect than PPA alone, and without developing tolerance. The PAP and PPA combination also showed a similar effect to PAP on REM sleep and was the treatment with the longest stage 2 and shortest SWS. No subjective sleep and awakening effects were seen during drug intake but subjective withdrawal reports were seen after abrupt interruption. The high agreement rate for the epoch-by-epoch comparison between automatic and human scoring confirms the validity of the Somnolyzer 24x7 and thus facilitates sleep studies in neuropsychopharmacological research.
Quantitative electroencephalographic (EEG) analysis is very useful for diagnosing dysfunctional n... more Quantitative electroencephalographic (EEG) analysis is very useful for diagnosing dysfunctional neural states and for evaluating drug effects on the brain, among others. However, the bidirectional contamination between electrooculographic (EOG) and cerebral activities can mislead and induce wrong conclusions from EEG recordings. Different methods for ocular reduction have been developed but only few studies have shown an objective evaluation of their performance. For this purpose, the following approaches were evaluated with simulated data: regression analysis, adaptive filtering, and blind source separation (BSS). In the first two, filtered versions were also taken into account by filtering EOG references in order to reduce the cancellation of cerebral high frequency components in EEG data. Performance of these methods was quantitatively evaluated by level of similarity, agreement and errors in spectral variables both between sources and corrected EEG recordings. Topographic distributions showed that errors were located at anterior sites and especially in frontopolar and lateral–frontal regions. In addition, these errors were higher in theta and especially delta band. In general, filtered versions of time-domain regression and of adaptive filtering with RLS algorithm provided a very effective ocular reduction. However, BSS based on second order statistics showed the highest similarity indexes and the lowest errors in spectral variables.
Eye movement artifacts represent a critical issue for quantitative electroencephalography (EEG) a... more Eye movement artifacts represent a critical issue for quantitative electroencephalography (EEG) analysis and a number of mathematical approaches have been proposed to reduce their contribution in EEG recordings. The aim of this paper was to objectively and quantitatively evaluate the performance of ocular filtering methods with respect to spectral target variables widely used in clinical and functional EEG studies. In particular the following methods were applied: regression analysis and some blind source separation (BSS) techniques based on second-order statistics (PCA, AMUSE and SOBI) and on higher-order statistics (JADE, INFOMAX and FASTICA). Considering blind source decomposition methods, a completely automatic procedure of BSS based on logical rules related to spectral and topographical information was proposed in order to identify the components related to ocular interference. The automatic procedure was applied in different montages of simulated EEG and electrooculography (EOG) recordings: a full montage with 19 EEG and 2 EOG channels, a reduced one with only 6 EEG leads and a third one where EOG channels were not available. Time and frequency results in all of them indicated that AMUSE and SOBI algorithms preserved and recovered more brain activity than the other methods mainly at anterior regions. In the case of full montage: (i) errors were lower than 5% for all spectral variables at anterior sites; and (ii) the highest improvement in the signal-to-artifact (SAR) ratio was obtained up to 40 dB at these anterior sites. Finally, we concluded that second-order BSS-based algorithms (AMUSE and SOBI) provided an effective technique for eye movement removal even when EOG recordings were not available or when data length was short. ᭧
Evaluation of an automatic ocular filtering method for awake spontaneous EEG signals based on independent component analysis
Electroencephalographic artifacts associated with eye movements are a potential source of error i... more Electroencephalographic artifacts associated with eye movements are a potential source of error in the EEG analysis when its interpretation is performed for evaluating the influence of drugs and the diagnosis of neurological disorders. In this study, a new automatic method for artifact filtering based on independent component analysis (ICA) is proposed. Automatic artifact identification is based on frequency domain and scalp topography aspects of the independent components. A comparative study between ICA and the 'gold standard' method based on linear regression analysis is performed. The latter does not take into account the mutual contamination between EEG and electrooculographic activity, reducing not only the ocular movements but also interesting cerebral activity, mainly in anteriorly placed electrodes. This limitation is overcome by ICA and the efficiency of this approach is shown for a double-blind, placebo-controlled crossover drug trial in healthy volunteers.
Reduction of EEG artifacts by ICA in different sleep stages
Contamination of sleep EEG signals by the eye, muscle and heart activity is a problem for EEG int... more Contamination of sleep EEG signals by the eye, muscle and heart activity is a problem for EEG interpretation and analysis of sleep disorders and influence of drugs. The aim of this paper is to evaluate a method of artifact reduction applied in different sleep stages: awakeness, stage 2, delta and REM sleep. Artifacts, particularly certain types, may be more likely found in particular settings and stages of sleep. To overcome the limitation of regression methods in bidirectional contamination, a method based on Independent Component Analysis (ICA) using time structure is applied. Artifact identification is based on time, frequency and scalp topography aspects of the independent components. Influence of artifacts is evaluated by calculating some target spectral variables before and after their reduction, using significance probability maps. Results show that ICA is a useful technique for the evaluation of these variables with clinical interest in different sleep stages.
Rationale Ayahuasca is a South American psychoactive plant tea which contains the serotonergic ps... more Rationale Ayahuasca is a South American psychoactive plant tea which contains the serotonergic psychedelic N,N-dimethyltryptamine (DMT) and monoamine-oxidase inhibitors that render DMT orally active. Previous investigations with ayahuasca have highlighted a psychotropic effect profile characterized by enhanced introspective attention, with individuals reporting altered somatic perceptions and intense emotional modifications, frequently accompanied by visual imagery. Despite recent advances in the study of ayahuasca pharmacology, the neural correlates of acute ayahuasca intoxication remain largely unknown. Objectives To investigate the effects of ayahuasca administration on regional cerebral blood flow. Methods Fifteen male volunteers with prior experience in the use of psychedelics received a single oral dose of encapsulated freeze-dried ayahuasca equivalent to 1.0 mg DMT/kg body weight and a placebo in a randomized double-blind clinical trial. Regional cerebral blood flow was measured 100–110 min after drug administration by means of single photon emission tomography (SPECT). Results Ayahuasca administration led to significant activation of frontal and paralimbic brain regions. Increased blood perfusion was observed bilaterally in the anterior insula, with greater intensity in the right hemisphere, and in the anterior cingulate/frontomedial cortex of the right hemisphere, areas previously implicated in somatic awareness, subjective feeling states, and emotional arousal. Additional increases were observed in the left amygdala/parahippocampal gyrus, a structure also involved in emotional arousal. Conclusions The present results suggest that ayahuasca interacts with neural systems that are central to interoception and emotional processing and point to a modulatory role of serotonergic neurotransmission in these processes.
Aspect-Oriented Programming enables developers to capture in separated aspect modules concerns th... more Aspect-Oriented Programming enables developers to capture in separated aspect modules concerns that are spread over different components in a system. This paper is an attempt to apply this paradigm to High Performance Computing. Besides achieving the usual advantages of improved modularity, more reusable code that is easier to develop and maintain, we pursue to improve efficiency by means of dynamic changes of aspects at runtime.
Objectives To compare the effects of typical and atypical antipsychotic drugs on sleep activity a... more Objectives To compare the effects of typical and atypical antipsychotic drugs on sleep activity and subjective sleep quality. Design Randomised, double-blind, placebo-controlled, four-period cross-over, clinical trial was used to evaluate the effects of active treatments on objective and subjective sleep variables. Setting Sleep laboratory evaluation. Participants Twenty healthy young volunteers, both sexes. Interventions Single oral morning administrations of olanzapine 5 mg, risperidone 1 mg, haloperidol 3 mg and placebo. Measurements and results Five polysomnographic nights were evaluated: one control night and one after each intervention. Significant increase in total sleep time, sleep efficiency, slow wave sleep (SWS) and rapid eye movement (REM) sleep with decreases in wake time were observed after olanzapine. Decreases in wake time, REM sleep and stage shifts together with increases in stage 2 were obtained after risperidone. Haloperidol showed only a tendency to increase sleep efficiency and stage 2 and to decrease wake time. Olanzapine showed decreases in power density in frequencies higher than 10 Hz during all sleep stages and in frequencies lower than 5 Hz range in SWS; decreases in the dynamics of spindle frequency activity (SFA) in the second and fourth non-rapid eye movement (NREM) episodes were also obtained. Risperidone presented increases in the 3.6–10.8 Hz frequency range in NREM sleep stages and in stage 2. Haloperidol also showed increases in NREM sleep stages and in stage 2, but these were in frequencies higher than 10 Hz, with increases in the dynamics of SFA in the first NREM episode. Only a significant improvement in subjective sleep quality was observed after olanzapine. Conclusions Antipsychotics showed different sleep changes as their neurochemical profiles were distinct. These changes were observed even when the drug was administered 15 h before going to bed.
Sleep Laboratory Study on Single and Repeated Dose Effects of Paroxetine, Alprazolam and Their Combination in Healthy Young Volunteers
Neuropsychobiology, 2005
To evaluate the potential interaction of 20 mg paroxetine and 1 mg alprazolam (early morning once... more To evaluate the potential interaction of 20 mg paroxetine and 1 mg alprazolam (early morning once-daily administration) on polysomnographic (PSG) sleep and subjective sleep and awakening quality, both after a single intake and after reaching a steady-state concentration. Twenty-two (11 for the PSG) healthy young volunteers of both sexes with no history of sleep disturbances (Pittsburgh Sleep Quality Index <5) participated in a double-blind, double-dummy, placebo-controlled, repeated-dose, 4-period, cross-over study. All volunteers received all 4 treatment sequences: paroxetine-alprazolam placebo (PAP); paroxetine placebo-alprazolam (PPA); paroxetine-alprazolam (PA), and paroxetine placebo-alprazolam placebo (PLA), in a randomized order. Each treatment was administered over 15 consecutive days, with a treatment-free interval of 7 days prior to the subsequent study period. In each experimental period, one PSG sleep study was performed on the 1st night (single-dose effects) and another study was performed on the 15th night (repeated-dose effects). Additionally, two other PSG studies were assessed: an adaptation recording, and a control night recording. All-night PSG recordings were obtained following standard procedures. Each 30-second period was scored according to the criteria of Rechtschaffen and Kales by means of an automatic sleep analysis system: Somnolyzer 24x7. A self-rating scale for sleep and awakening quality and early morning behavior was completed no later than 15 min after awakening over the 15 days of each experimental intervention. General lineal models (treatment/time) were applied separately to each variable. (1) No significant effects were observed in any sleep variables when control nights were compared with the 1st night with PLA. (2) Sleep continuity: After PAP a clear awakening effect was seen both in the first and second evaluations, mainly in wake time, movement time, number of awakenings and stage-1 duration. After PPA an evident hypnotic effect was observed on night 1. This effect was mainly observed in maintenance variables and slightly in sleep initiation variables; it had decreased by night 15. After PA an intermediate behavior in the variables related to sleep continuity was seen, highlighting the absence of the tolerance phenomenon observed when PPA was administered alone. (3) Sleep architecture: The most important effects in REM sleep were observed after PAP; an increase in REM latency and decreases in REM sleep. PAP also induced decreases in the number of non-REM and REM periods and increases in the average duration of non-REM periods and sleep cycles. PA presented a similar pattern to PAP, and PPA similar to PLA. In relation to non-REM sleep, PA showed more stage-2 and less slow-wave sleep (SWS). (4) Subjective perception: No significant differences were observed between treatments while they were being taken, but impairments in subjective sleep quality, awaking quality, latency and efficiency were seen, mainly after PA but also after PPA discontinuations. The combination of PAP and PPA presented an intermediate pattern in relation to sleep continuity, with less awaking effect than PAP alone and less hypnotic effect than PPA alone, and without developing tolerance. The PAP and PPA combination also showed a similar effect to PAP on REM sleep and was the treatment with the longest stage 2 and shortest SWS. No subjective sleep and awakening effects were seen during drug intake but subjective withdrawal reports were seen after abrupt interruption. The high agreement rate for the epoch-by-epoch comparison between automatic and human scoring confirms the validity of the Somnolyzer 24x7 and thus facilitates sleep studies in neuropsychopharmacological research.
Quantitative electroencephalographic (EEG) analysis is very useful for diagnosing dysfunctional n... more Quantitative electroencephalographic (EEG) analysis is very useful for diagnosing dysfunctional neural states and for evaluating drug effects on the brain, among others. However, the bidirectional contamination between electrooculographic (EOG) and cerebral activities can mislead and induce wrong conclusions from EEG recordings. Different methods for ocular reduction have been developed but only few studies have shown an objective evaluation of their performance. For this purpose, the following approaches were evaluated with simulated data: regression analysis, adaptive filtering, and blind source separation (BSS). In the first two, filtered versions were also taken into account by filtering EOG references in order to reduce the cancellation of cerebral high frequency components in EEG data. Performance of these methods was quantitatively evaluated by level of similarity, agreement and errors in spectral variables both between sources and corrected EEG recordings. Topographic distributions showed that errors were located at anterior sites and especially in frontopolar and lateral–frontal regions. In addition, these errors were higher in theta and especially delta band. In general, filtered versions of time-domain regression and of adaptive filtering with RLS algorithm provided a very effective ocular reduction. However, BSS based on second order statistics showed the highest similarity indexes and the lowest errors in spectral variables.
Eye movement artifacts represent a critical issue for quantitative electroencephalography (EEG) a... more Eye movement artifacts represent a critical issue for quantitative electroencephalography (EEG) analysis and a number of mathematical approaches have been proposed to reduce their contribution in EEG recordings. The aim of this paper was to objectively and quantitatively evaluate the performance of ocular filtering methods with respect to spectral target variables widely used in clinical and functional EEG studies. In particular the following methods were applied: regression analysis and some blind source separation (BSS) techniques based on second-order statistics (PCA, AMUSE and SOBI) and on higher-order statistics (JADE, INFOMAX and FASTICA). Considering blind source decomposition methods, a completely automatic procedure of BSS based on logical rules related to spectral and topographical information was proposed in order to identify the components related to ocular interference. The automatic procedure was applied in different montages of simulated EEG and electrooculography (EOG) recordings: a full montage with 19 EEG and 2 EOG channels, a reduced one with only 6 EEG leads and a third one where EOG channels were not available. Time and frequency results in all of them indicated that AMUSE and SOBI algorithms preserved and recovered more brain activity than the other methods mainly at anterior regions. In the case of full montage: (i) errors were lower than 5% for all spectral variables at anterior sites; and (ii) the highest improvement in the signal-to-artifact (SAR) ratio was obtained up to 40 dB at these anterior sites. Finally, we concluded that second-order BSS-based algorithms (AMUSE and SOBI) provided an effective technique for eye movement removal even when EOG recordings were not available or when data length was short. ᭧
Evaluation of an automatic ocular filtering method for awake spontaneous EEG signals based on independent component analysis
Electroencephalographic artifacts associated with eye movements are a potential source of error i... more Electroencephalographic artifacts associated with eye movements are a potential source of error in the EEG analysis when its interpretation is performed for evaluating the influence of drugs and the diagnosis of neurological disorders. In this study, a new automatic method for artifact filtering based on independent component analysis (ICA) is proposed. Automatic artifact identification is based on frequency domain and scalp topography aspects of the independent components. A comparative study between ICA and the 'gold standard' method based on linear regression analysis is performed. The latter does not take into account the mutual contamination between EEG and electrooculographic activity, reducing not only the ocular movements but also interesting cerebral activity, mainly in anteriorly placed electrodes. This limitation is overcome by ICA and the efficiency of this approach is shown for a double-blind, placebo-controlled crossover drug trial in healthy volunteers.
Reduction of EEG artifacts by ICA in different sleep stages
Contamination of sleep EEG signals by the eye, muscle and heart activity is a problem for EEG int... more Contamination of sleep EEG signals by the eye, muscle and heart activity is a problem for EEG interpretation and analysis of sleep disorders and influence of drugs. The aim of this paper is to evaluate a method of artifact reduction applied in different sleep stages: awakeness, stage 2, delta and REM sleep. Artifacts, particularly certain types, may be more likely found in particular settings and stages of sleep. To overcome the limitation of regression methods in bidirectional contamination, a method based on Independent Component Analysis (ICA) using time structure is applied. Artifact identification is based on time, frequency and scalp topography aspects of the independent components. Influence of artifacts is evaluated by calculating some target spectral variables before and after their reduction, using significance probability maps. Results show that ICA is a useful technique for the evaluation of these variables with clinical interest in different sleep stages.
Rationale Ayahuasca is a South American psychoactive plant tea which contains the serotonergic ps... more Rationale Ayahuasca is a South American psychoactive plant tea which contains the serotonergic psychedelic N,N-dimethyltryptamine (DMT) and monoamine-oxidase inhibitors that render DMT orally active. Previous investigations with ayahuasca have highlighted a psychotropic effect profile characterized by enhanced introspective attention, with individuals reporting altered somatic perceptions and intense emotional modifications, frequently accompanied by visual imagery. Despite recent advances in the study of ayahuasca pharmacology, the neural correlates of acute ayahuasca intoxication remain largely unknown. Objectives To investigate the effects of ayahuasca administration on regional cerebral blood flow. Methods Fifteen male volunteers with prior experience in the use of psychedelics received a single oral dose of encapsulated freeze-dried ayahuasca equivalent to 1.0 mg DMT/kg body weight and a placebo in a randomized double-blind clinical trial. Regional cerebral blood flow was measured 100–110 min after drug administration by means of single photon emission tomography (SPECT). Results Ayahuasca administration led to significant activation of frontal and paralimbic brain regions. Increased blood perfusion was observed bilaterally in the anterior insula, with greater intensity in the right hemisphere, and in the anterior cingulate/frontomedial cortex of the right hemisphere, areas previously implicated in somatic awareness, subjective feeling states, and emotional arousal. Additional increases were observed in the left amygdala/parahippocampal gyrus, a structure also involved in emotional arousal. Conclusions The present results suggest that ayahuasca interacts with neural systems that are central to interoception and emotional processing and point to a modulatory role of serotonergic neurotransmission in these processes.
Objectives To compare the effects of typical and atypical antipsychotic drugs on sleep activity a... more Objectives To compare the effects of typical and atypical antipsychotic drugs on sleep activity and subjective sleep quality. Design Randomised, double-blind, placebo-controlled, four-period cross-over, clinical trial was used to evaluate the effects of active treatments on objective and subjective sleep variables. Setting Sleep laboratory evaluation. Participants Twenty healthy young volunteers, both sexes. Interventions Single oral morning administrations of olanzapine 5 mg, risperidone 1 mg, haloperidol 3 mg and placebo. Measurements and results Five polysomnographic nights were evaluated: one control night and one after each intervention. Significant increase in total sleep time, sleep efficiency, slow wave sleep (SWS) and rapid eye movement (REM) sleep with decreases in wake time were observed after olanzapine. Decreases in wake time, REM sleep and stage shifts together with increases in stage 2 were obtained after risperidone. Haloperidol showed only a tendency to increase sleep efficiency and stage 2 and to decrease wake time. Olanzapine showed decreases in power density in frequencies higher than 10 Hz during all sleep stages and in frequencies lower than 5 Hz range in SWS; decreases in the dynamics of spindle frequency activity (SFA) in the second and fourth non-rapid eye movement (NREM) episodes were also obtained. Risperidone presented increases in the 3.6–10.8 Hz frequency range in NREM sleep stages and in stage 2. Haloperidol also showed increases in NREM sleep stages and in stage 2, but these were in frequencies higher than 10 Hz, with increases in the dynamics of SFA in the first NREM episode. Only a significant improvement in subjective sleep quality was observed after olanzapine. Conclusions Antipsychotics showed different sleep changes as their neurochemical profiles were distinct. These changes were observed even when the drug was administered 15 h before going to bed.
Sleep Laboratory Study on Single and Repeated Dose Effects of Paroxetine, Alprazolam and Their Combination in Healthy Young Volunteers
Neuropsychobiology, 2005
To evaluate the potential interaction of 20 mg paroxetine and 1 mg alprazolam (early morning once... more To evaluate the potential interaction of 20 mg paroxetine and 1 mg alprazolam (early morning once-daily administration) on polysomnographic (PSG) sleep and subjective sleep and awakening quality, both after a single intake and after reaching a steady-state concentration. Twenty-two (11 for the PSG) healthy young volunteers of both sexes with no history of sleep disturbances (Pittsburgh Sleep Quality Index <5) participated in a double-blind, double-dummy, placebo-controlled, repeated-dose, 4-period, cross-over study. All volunteers received all 4 treatment sequences: paroxetine-alprazolam placebo (PAP); paroxetine placebo-alprazolam (PPA); paroxetine-alprazolam (PA), and paroxetine placebo-alprazolam placebo (PLA), in a randomized order. Each treatment was administered over 15 consecutive days, with a treatment-free interval of 7 days prior to the subsequent study period. In each experimental period, one PSG sleep study was performed on the 1st night (single-dose effects) and another study was performed on the 15th night (repeated-dose effects). Additionally, two other PSG studies were assessed: an adaptation recording, and a control night recording. All-night PSG recordings were obtained following standard procedures. Each 30-second period was scored according to the criteria of Rechtschaffen and Kales by means of an automatic sleep analysis system: Somnolyzer 24x7. A self-rating scale for sleep and awakening quality and early morning behavior was completed no later than 15 min after awakening over the 15 days of each experimental intervention. General lineal models (treatment/time) were applied separately to each variable. (1) No significant effects were observed in any sleep variables when control nights were compared with the 1st night with PLA. (2) Sleep continuity: After PAP a clear awakening effect was seen both in the first and second evaluations, mainly in wake time, movement time, number of awakenings and stage-1 duration. After PPA an evident hypnotic effect was observed on night 1. This effect was mainly observed in maintenance variables and slightly in sleep initiation variables; it had decreased by night 15. After PA an intermediate behavior in the variables related to sleep continuity was seen, highlighting the absence of the tolerance phenomenon observed when PPA was administered alone. (3) Sleep architecture: The most important effects in REM sleep were observed after PAP; an increase in REM latency and decreases in REM sleep. PAP also induced decreases in the number of non-REM and REM periods and increases in the average duration of non-REM periods and sleep cycles. PA presented a similar pattern to PAP, and PPA similar to PLA. In relation to non-REM sleep, PA showed more stage-2 and less slow-wave sleep (SWS). (4) Subjective perception: No significant differences were observed between treatments while they were being taken, but impairments in subjective sleep quality, awaking quality, latency and efficiency were seen, mainly after PA but also after PPA discontinuations. The combination of PAP and PPA presented an intermediate pattern in relation to sleep continuity, with less awaking effect than PAP alone and less hypnotic effect than PPA alone, and without developing tolerance. The PAP and PPA combination also showed a similar effect to PAP on REM sleep and was the treatment with the longest stage 2 and shortest SWS. No subjective sleep and awakening effects were seen during drug intake but subjective withdrawal reports were seen after abrupt interruption. The high agreement rate for the epoch-by-epoch comparison between automatic and human scoring confirms the validity of the Somnolyzer 24x7 and thus facilitates sleep studies in neuropsychopharmacological research.
Quantitative electroencephalographic (EEG) analysis is very useful for diagnosing dysfunctional n... more Quantitative electroencephalographic (EEG) analysis is very useful for diagnosing dysfunctional neural states and for evaluating drug effects on the brain, among others. However, the bidirectional contamination between electrooculographic (EOG) and cerebral activities can mislead and induce wrong conclusions from EEG recordings. Different methods for ocular reduction have been developed but only few studies have shown an objective evaluation of their performance. For this purpose, the following approaches were evaluated with simulated data: regression analysis, adaptive filtering, and blind source separation (BSS). In the first two, filtered versions were also taken into account by filtering EOG references in order to reduce the cancellation of cerebral high frequency components in EEG data. Performance of these methods was quantitatively evaluated by level of similarity, agreement and errors in spectral variables both between sources and corrected EEG recordings. Topographic distributions showed that errors were located at anterior sites and especially in frontopolar and lateral–frontal regions. In addition, these errors were higher in theta and especially delta band. In general, filtered versions of time-domain regression and of adaptive filtering with RLS algorithm provided a very effective ocular reduction. However, BSS based on second order statistics showed the highest similarity indexes and the lowest errors in spectral variables.
Eye movement artifacts represent a critical issue for quantitative electroencephalography (EEG) a... more Eye movement artifacts represent a critical issue for quantitative electroencephalography (EEG) analysis and a number of mathematical approaches have been proposed to reduce their contribution in EEG recordings. The aim of this paper was to objectively and quantitatively evaluate the performance of ocular filtering methods with respect to spectral target variables widely used in clinical and functional EEG studies. In particular the following methods were applied: regression analysis and some blind source separation (BSS) techniques based on second-order statistics (PCA, AMUSE and SOBI) and on higher-order statistics (JADE, INFOMAX and FASTICA). Considering blind source decomposition methods, a completely automatic procedure of BSS based on logical rules related to spectral and topographical information was proposed in order to identify the components related to ocular interference. The automatic procedure was applied in different montages of simulated EEG and electrooculography (EOG) recordings: a full montage with 19 EEG and 2 EOG channels, a reduced one with only 6 EEG leads and a third one where EOG channels were not available. Time and frequency results in all of them indicated that AMUSE and SOBI algorithms preserved and recovered more brain activity than the other methods mainly at anterior regions. In the case of full montage: (i) errors were lower than 5% for all spectral variables at anterior sites; and (ii) the highest improvement in the signal-to-artifact (SAR) ratio was obtained up to 40 dB at these anterior sites. Finally, we concluded that second-order BSS-based algorithms (AMUSE and SOBI) provided an effective technique for eye movement removal even when EOG recordings were not available or when data length was short. ᭧
Evaluation of an automatic ocular filtering method for awake spontaneous EEG signals based on independent component analysis
Electroencephalographic artifacts associated with eye movements are a potential source of error i... more Electroencephalographic artifacts associated with eye movements are a potential source of error in the EEG analysis when its interpretation is performed for evaluating the influence of drugs and the diagnosis of neurological disorders. In this study, a new automatic method for artifact filtering based on independent component analysis (ICA) is proposed. Automatic artifact identification is based on frequency domain and scalp topography aspects of the independent components. A comparative study between ICA and the 'gold standard' method based on linear regression analysis is performed. The latter does not take into account the mutual contamination between EEG and electrooculographic activity, reducing not only the ocular movements but also interesting cerebral activity, mainly in anteriorly placed electrodes. This limitation is overcome by ICA and the efficiency of this approach is shown for a double-blind, placebo-controlled crossover drug trial in healthy volunteers.
Reduction of EEG artifacts by ICA in different sleep stages
Contamination of sleep EEG signals by the eye, muscle and heart activity is a problem for EEG int... more Contamination of sleep EEG signals by the eye, muscle and heart activity is a problem for EEG interpretation and analysis of sleep disorders and influence of drugs. The aim of this paper is to evaluate a method of artifact reduction applied in different sleep stages: awakeness, stage 2, delta and REM sleep. Artifacts, particularly certain types, may be more likely found in particular settings and stages of sleep. To overcome the limitation of regression methods in bidirectional contamination, a method based on Independent Component Analysis (ICA) using time structure is applied. Artifact identification is based on time, frequency and scalp topography aspects of the independent components. Influence of artifacts is evaluated by calculating some target spectral variables before and after their reduction, using significance probability maps. Results show that ICA is a useful technique for the evaluation of these variables with clinical interest in different sleep stages.
Rationale Ayahuasca is a South American psychoactive plant tea which contains the serotonergic ps... more Rationale Ayahuasca is a South American psychoactive plant tea which contains the serotonergic psychedelic N,N-dimethyltryptamine (DMT) and monoamine-oxidase inhibitors that render DMT orally active. Previous investigations with ayahuasca have highlighted a psychotropic effect profile characterized by enhanced introspective attention, with individuals reporting altered somatic perceptions and intense emotional modifications, frequently accompanied by visual imagery. Despite recent advances in the study of ayahuasca pharmacology, the neural correlates of acute ayahuasca intoxication remain largely unknown. Objectives To investigate the effects of ayahuasca administration on regional cerebral blood flow. Methods Fifteen male volunteers with prior experience in the use of psychedelics received a single oral dose of encapsulated freeze-dried ayahuasca equivalent to 1.0 mg DMT/kg body weight and a placebo in a randomized double-blind clinical trial. Regional cerebral blood flow was measured 100–110 min after drug administration by means of single photon emission tomography (SPECT). Results Ayahuasca administration led to significant activation of frontal and paralimbic brain regions. Increased blood perfusion was observed bilaterally in the anterior insula, with greater intensity in the right hemisphere, and in the anterior cingulate/frontomedial cortex of the right hemisphere, areas previously implicated in somatic awareness, subjective feeling states, and emotional arousal. Additional increases were observed in the left amygdala/parahippocampal gyrus, a structure also involved in emotional arousal. Conclusions The present results suggest that ayahuasca interacts with neural systems that are central to interoception and emotional processing and point to a modulatory role of serotonergic neurotransmission in these processes.
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Papers by Sergio Romero