Hypofunction of N-methyl-d-aspartate receptors (NMDARs) has been associated with deficits in synaptic plasticity and cognitive decline as found in neuropsychiatric and neurodegenerative disorders such as Alzheimer’s disease. Glycine and D-serine are endogenous ligands of the NMDAR and therapeutic approaches that enhance NMDAR activity through increases in glycine and/or D-serine levels are expected to enhance synaptic strength and to potentially improve have impact on cognition processes.
The present in-vivo study investigated whether positive modulation of brain glycine levels, through modulation by the glycine transporter 1 (GlyT1) inhibitor SSR504734, affects network connectivity and long-term potentiation (LTP) at the hippocampus. For in-vivo network oscillations and connectivity, multichannel EEG recordings were performed in conscious Sprague–Dawley rats from frontal cortical, hippocampal CA1 and CA3 and dentate gyrus (DG) structures after subcutaneous administration of vehicle or SSR504734 (2.5, 10 and 40 mg/kg). For hippocampal synaptic plasticity, rats were anesthetized with urethane and recording and stimulating electrodes were inserted at the DG and at the medial perforant pathway (MPP), respectively. Population spike (PS) amplitudes (PSA) and excitatory postsynaptic potential (EPSP) slope were measured before and 2-h after high-frequency stimulation (HFS).
SSR504734 (at 40 mg/kg) elicited robust EEG slow theta oscillations (4–6.5 Hz) at the DG, CA1 and CA3 and in addition slow gamma oscillations (30-50Hz) in the frontal areas, next to network coherence changes between frontal and CA1 recording sites, which were dissociated from motor behavior. SSR504734 (at 40 mg/kg) enhanced LTP of the PS amplitude after HFS of the MPP synapse, whereas the potentiation of EPSP slope was short-lived.
The present data support the hypothesis on a facilitating role of the NMDARs glycine binding site on network oscillations and synaptic efficacy at the medial perforant path of the DG. Future studies will evaluate novel approaches targeting D-Serine modulatory sites, for example by inhibition of the enzyme d-amino acid oxidase (DAAO), which slows the break-down of D-serine, or by its transporter, the alanine-serine-cysteine-1 (Asc-1), the abnormal glio-transmission of which has been linked to synaptic failure in Alzheimer’s disease.
Withdrawn
Dyslexia is amongst the commonest of neurobiological disorders, affecting about 20 % of children in Norway. Its heterogeneity makes it difficult to establish a single treatment which is suitable for most of the affected. According to the phonological theory of dyslexia, the disorder is caused by a deficit in the representation, storage and recall of speech sounds. Different brain areas have been linked to the phonological deficit by means of different brain imaging techniques, among other quantitative electroencephalography (qEEG).
The aim of this study was to improve reading ability in children with dyslexia by means of individualized neurofeedback training. The study was conducted as a pre-post intervention single-subject design with 5 participants, aged from 13 to 14 years. The intervention consisted of 25 sessions of neurofeedback training, 15 beta/theta frontocentral sessions and 10 individualized sessions, mostly towards the language areas. The effect of the intervention was measured by means of qEEG and the LOGOS (a Norwegian dyslexia assessment battery).
The results showed improvement in reading abilities and phonological skills amongst all participants. Furthermore, qEEG analysis showed increased alpha activity in several brain areas, and normalization of theta and beta activity in comparison to a normative database. An increase of alpha activity may possibly indicate changes in alpha coherence which can be an indication of improved attentional processes. This may explain the improvements in reading and phonological skills. The analysis also confirms the heterogeneity of dyslexia, and the complicity of several brain areas that are involved in dyslexia.
This study is limited by the small number of participants, and the restriction in time (the number of training sessions offered). However, the improvement in reading and phonological skills in this study suggests that neurofeedback training may be an effective and relevant intervention for adolescents with dyslexia. But, further research in this area with larger samples and a larger number of training sessions is required.
The study was approved by the regional ethics committee.
Competing interests
There are no competing interests.
Background
The auditory MMN (mismatch negativity) is considered to be an index of automatic context-dependent information processing and auditory sensory memory. MMN deficit is a characteristic endophenotype of schizophrenia. A 5-HT2A agonist psilocybin induces acute transient psychotic symptoms and is extensively used as a putative pharmacological model of schizophrenia. Our aim was to investigate the effect of psilocybin on this pre-attentive cognitive functions.
Methods
A double-blind, placebo controlled study design was used. 20 healthy adult volunteers were administered a dose of psilocybin (0,26 mg/kg) and placebo per os in 2 separate sessions. Auditory MMN was recorded in sound and electrically shielded room, 120 min after ingestion of psilocybin/placebo. Participants were lying down with their eyes closed in a comfortable setting with two sitters who were present during whole experiment.
MMN
A single deviant paradigm with 1350 standard (1000Hz, 75 dB SPL, 100 ms duration) and 75 deviant in frequency (1200Hz, 75 dB SPL, 100 ms) tones were presented binaurally in regular order when every 20th was deviant tone. Data was acquired with a standard 32-channel digital EEG amplifier BrainScope (unimedis, Prague) with 21 Ag/AgCl scalp electrodes placed according to the 10/20 system and sampled at 1000 Hz.
Results
Mismatch negativity was calculated by subtracting the average of frequently occurring stimuli from the average of deviants. There were no significant differences in latency, absolute amplitude and area under curve of MMN during psilocybin intoxication compared to placebo. Furthermore, there were no correlations between subjective effects induced by psilocybin (HRS and ASCS) and MMN.
Conclusion
Our results correspond with previous findings [1]. Psilocybin does not affect processing at the level of pre-attentive cognition and the auditory sensory memory.
This effect is probably due to different underlying receptor mechanism as the generation of MMN is strongly dependent on NMDAR dysfunction. Another reason for negative results could be inappropriate timing of recording or insufficient single-deviant paradigm.
This work is supported by Ministry of Health of the Czech Republic, grant nr. 15-29900A. All rights reserved.
References
1. Umbricht D, Vollenweider F X, Schmid L, Grübel C, Skrabo A, Huber R et Koller R. Effects of 5-HT2A agonist Psilocybin on Mismatch Negativity generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia. Neuropsychopharmacology 2003;Jan;28(1):170–81
Background
About 5 % of school-aged children may have an Attention Deficit-Hyperactivity Disorder (ADHD), a neurodevelopmental disorder often associated with other comorbid conditions including sleep disorders. ADHD became a public health concern. Psychostimulants are the first line pharmacological treatments for ADHD. However, parents are often reluctant to medicate their children and, additionally, a proportion of patients stop their treatment because of side effects. Non-pharmacological treatments are also available. Recently, improvements of cognitive functioning and hyperactivity level of patients with ADHD have been reported after Neurofeedback trainings with a relative Upper Alpha Power enhancement paradigm. Sensorimotor rhythm (SMR) Neurofeedback has been also proposed to improve ADHD symptoms. The aim of this study is to compare the benefits of Upper Alpha and SMR trainings on ADHD symptoms and concomitant improvement of sleep.
Methods
In this controlled and randomized study, 60 French medication-free children and adolescents with ADHD aged from 8 to 15 years old will participate in 30 neurofeedback sessions. They will be assigned to either in either the SMR or the Upper Alpha training group. EEG, ADHD rating scales, cognitive assessment, and actigraphic records will be performed at pre-, mid- and post-training times, and 6 months after the end of protocol.
Results
The main expected outcome is the clinical reduction of at least 30 % of ADHD symptoms, and we anticipated the superiority of Upper Alpha training over SMR in reducing hyperactivity levels. Improvement of sleep quality is a secondary outcome.
Conclusion
To date, no comparison between SMR and Upper Alpha Neurofeedback trainings with a significant number of sessions and enough patients in each group has been conducted. We hope to gain valuable insights into specific effects of both trainings on ADHD symptoms and sleep without any medication. This study would foster the development of research on Neurofeedback and its clinical applications, which are under-investigated in France.
Trial Registration
N°ID RCB 2016-A00655-46
Keywords
ADHD, Neurofeedback, SMR-Upper Alpha Training, EEG, non pharmacological treatment, sleep disorders
Background
Mind body based meditation techniques called Tai-Chi Chuan (TCC, a moving meditation) [1] and Cyclic Meditation (CM, a stimulation and relaxation meditation) [2] has been proven to reshape the patterns of brain structures and functional connectivity. TCC practices showed improvement in the brain functions associated with cognition, behavior and health [3]. Similarly, CM also reported improvement in midbrain region [4] associated with better information processing speed or improved motor speed [5].
Method and materials
We evaluated the effect of Tai-Chi Chuan (TCC, a Chines movement based meditation technique) and Cyclic Meditation (CM, an Indian traditional based stimulation and relaxation meditation technique) on the hemodynamic responses of the prefrontal cortex (PFC) activity and autonomic functions (such as R-R interval (RR-I of heart rate variability and respiration). These two meditation practices were compared with simple walking. Employing 64 channel near infrared spectroscopy (NIRS), we measured hemoglobin concentration change (i.e., Oxyhemoglobin [DHbO], Deoxyhemoglobin [DHbR] and Total hemoglobin change [DTHC]) in the bilateral PFC before and after TCC, CM and Walking in young college students (n = 25; average mean age ± SD; 23.4 ± 3.1 years).
Results
We observed the left PFC activity predominantly modulates sympathetic activity effects during the Tai-Chi whereas CM showed changes on right PFC with vagal dominance. However, the changes in oxyhemoglobin and total blood volume change after Tai-Chi was significant higher (p < 0.05, spm t-maps) on left hemisphere, whereas after CM, there were a significant increase in oxyhemoglobin (p < 0.01) with a decrease in deoxyhemoglobin (p < 0.05) on right PFC. The normal walking showed decrease in Oxyhemoglobin with increase in deoxyhemoglobin on left PFC. The autonomic functions result showed a significant increase in RR- interval (p < 0.05) along with significant reduction in HR (p < 0.05) in CM whereas Tai-chi session showed significant increase in HR (p < 0.05) when compared to walking session. Within group analysis showed a significant reduction in RR-I and significant increase in HR both in Tai-chi and walking sessions. The CM showed there were a significant improvement in RR-interval of HRV (p < 0.01) with reduction of heart rate and breath rate (p < 0.05).
Conclusions
The result suggested that Tai-Chi and CM both have positive effect on left and right prefrontal cortex and increase sympathovagal balance (alertful rest) in autonomic nervous system activity.
Keywords
Tai-Chi-Chuan (TCC); Yoga; Cyclic Meditation (CM); Walking; Prefrontal Cortex (PFC); Heart Rate Variability (HRV)
References
1. J. L. W. Robins, R. K. Elswick, and N. L. McCain, “The story of the evolution of a unique tai chi form: origins, philosophy, and research.,” J. Holist. Nurs., vol. 30, no. 3, pp. 134–46, 2012.
2. P. Subramanya and S. Telles, “A review of the scientific studies on cyclic meditation.,” Int. J. Yoga, vol. 2, no. 2, pp. 46–48, Jul. 2009.
3. G.-X. Wei, H.-M. Dong, Z. Yang, J. Luo, and X.-N. Zuo, “Tai Chi Chuan optimizes the functional organization of the intrinsic human brain architecture in older adults.,” Front. Aging Neurosci., vol. 6, p. 74, Jan. 2014.
4. P. Subramanya and S. Telles, “Changes in midlatency auditory evoked potentials following two yoga-based relaxation techniques.,” Clin. EEG Neurosci., vol. 40, no. 3, pp. 190–5, Jul. 2009.
5. P. Subramanya and S. Telles, “Performance on psychomotor tasks following two yoga-based relaxation techniques.,” Percept. Mot. Skills, vol. 109, no. 2, pp. 563–76, Oct. 2009.
Withdrawn
Efficacy testing of plant-derived and homeopathic drugs still remains a challenge in pharmacology. In the past several neurophysiological techniques have been successfully applied. However, interpretation of spectral power values with respect to different brain regions is contradictory. Conventional quantitative EEG analysis uses averaged data from epochs of 2 or 4 s. Analysis of shorter epoch length of 364 ms has been achieved by definition of specific frequency ranges [1]. Surprisingly, focal spectral power within these short periods reached tremendous values (up to 9000 %) at single brain regions when compared to the average of other assessed regions (global median) [2]. In order to learn more about these short periods of high electric activity, EEG analysis was combined with eye tracking. The eye tracking software served to present different cognitive and emotional audio-visual challenges in series. Synchronization of the gaze overlay video from the eye tracking with screen capture of the online quantitative EEG analysis was achieved by starting the recording with a gong. The combined technology has been published [3]. Synchronized scenes were evaluated before and after intake of the preparations. In the presence of cognition activating drugs (i.e. Zembrin®) more flashing of delta (1.375 – 4.125 Hz) and theta spectral power (4.125 – 6.875 Hz) was observed in frontal brain in comparison to placebo during performance of psychometric testing. In the presence of calming drugs (i.e. plant-derived drug Pascoflair®) more flashing of alpha1 spectral power (6.875 – 9.625 Hz) was recognized in comparison to placebo. The same increase of spectral alpha1 power was detected after intake of 6 homeopathic Calmvalera Hevert tablets at a time. Since about 3 pictures per second are difficult to follow, slow motion videos will be presented. Finally, averaged data were fed into a discriminant analysis. Comparison of several plant-derived and homeopathic drugs with each other revealed for example projection of data from 3 calming drugs in close vicinity to each other.
References
1. Dimpfel, W., Hofmann, H-C. (2014) Neurocode-Tracking Based on Quantitative Fast Dynamic EEG Recording in Combination with Eye-Tracking. World Journal of Neuroscience 4, 106–119.
2. Dimpfel, W., Chiegoua Dipah, G.N., Gericke, N. (2016) EnkephaloVision: Anatomical Functionality Indicated by Ultrashort Transient Regional EEG Spectral Power Changes during Cognitive and Emotional Challenges. World Journal of Neuroscience, 6, 90–108.
3. Dimpfel, W. (2015) Drug Discovery and Translational Medicine Based on Neurophysiological Techniques. A holistic approach to saving animals. Verlag Books on Demand, Norderstedt, Germany.
Several studies have demonstrated abnormalities in quantitative electroencephalogram (qEEG) in children and adults with ADHD. Based on these findings, neurofeedback training (NFT) has emerged has a new treatment option for ADHD. In this preliminary study, qEEG was used to assess the efficacy of NFT training for college students with ADHD. Participants received computer attention training intervention using NFT two times a week over a period of four months. A group of college students with ADHD who did not undergo NFT training was used as a control group. Brain activity was measured using qEEG prior to, midway through, and post NFT training. ADHD behavioral symptoms were also assessed pre- and post- training using the Conners’ Adult ADHD Rating Scale (CAARS-S:L) and the IVA-2. Changes in qEEG were detected following NFT. Significant changes in resting-state brain activity were observed in the experimental group. Participants who underwent training demonstrated significant decreases in absolute power across a wide spectrum of frequency bands (delta, theta, alpha and beta) as well as a relative decrease in alpha activity and increase in delta and beta activity. In order to identify if anomalous patterns of brain activity were related to symptoms of ADHD, neuroelectric measures were compared to behavioral measures. Changes in neural activity in the experimental group correlate with improvements in ADHD symptoms. Although further research is warranted to determine the exact impact of NFT on the neural correlates of ADHD, these preliminary findings suggest that it might be a promising cognitive training treatment for students with ADHD.
Keywords
qEEG, neurofeedback, ADHD, ADD
Movement disorders represent a group of neurological syndromes characterised by an alteration of voluntary and/or automatic movements. Here, we focused on Parkinson’s disease (PD) and essential tremor (ET), which are the most common forms of movement disorders.
Motor symptoms of Parkinson’s disease result from a dysfunction of cortico-basal ganglia circuits mainly due to dopaminergic neurons death in the substantia nigra pars compacta. A hypersynchronization of beta frequency oscillatory activity in these circuits has been described in both patients and animal models of the disease.
Essential tremor (ET) is characterized by the symptom of action tremor (which intensifies when the affected muscles are used). ET typically involves a tremor of the arms, hands or fingers. The classically-used animal model of ET is generated by the administration of the beta-carbolin harmaline in mice. Harmaline induces action tremors lasting several hours and the classical read-out is the recording of behavioural tremor frequency that occurs between 8 to 10Hz.
The aim of this poster was to provide two examples of the use of brain oscillations in preclinical drug development for movement disorders. Here, 1) we assessed the use of aberrant cortical oscillations in the unilateral 6-OHDA injected rat as translational biomarkers for drug development in PD, and 2) studied the effect of harmaline-induced tremor on cortical and cerebellar oscillatory activities. The sensitivity of these functional biomarkers was challenged with the reference drugs for each pathology.
In the 6-OHDA rat model of PD, we found a prominent beta band (~30Hz) in the motor cortex, which was inexistent in control Sprague–Dawley rats. Acute injection of the dopaminergic receptor agonist L-DOPA (6 and 20 mg/kg) induced body rotations along with a significant reduction of the beta band. This treatment also induced a prominent 80-100Hz gamma increase. By contrast, the D2/D3/D4 agonist ropinirole at 0.2, 0.4, and 0.8 mg/kg also decreased the beta band but caused only a slight gamma band increase.
We found that administration of harmaline (10-20-30 mg/kg) in male C57BL/6 J mice dose-dependently increased the cortical and cerebellar power in a wide 15-60Hz frequency range, along with action tremors. Pre-treatment with 20 mg/kg propranolol, one of the first-line medications used in ET patients attenuated the tremors and decreased the 35-60Hz range.
In this study, we identified aberrant EEG oscillations in two rodent models of movement disorders. These oscillations and their pharmacological modulation may represent predictive biomarkers for the identification, selection and validation of new therapeutics in movement disorders.
Dopamine is a key regulator of cognition, mood, reward and movement in the human and rodent brain. The dopamine homeostasis is tightly controlled by the dopamine transporter (DAT), which is a target for addictive drugs (such as cocaine and amphetamine), and therapeutic antidepressants.
The present study was designed to investigate the effects of cocaine in freely moving rats using telemetric electroencephalography (EEG) to monitor a hyperdopaminergic state. Additionally, in vivo microdialysis in the nucleus accumbens shell was carried out to measure extracellular cocaine levels and dopamine itself by LC-MS-MS and HPLC coupled to electrochemical detection. Behaviour was assessed by an automated motor activity system using light beam interruptions.
Cocaine (5, 10 and 15 mg/kg, i.p.) dose dependently induced an increase in motor activity, which reached its maximum level after 20 min and lasted for 90 min. In addition, cocaine appeared to affect the EEG power spectrum, increasing gamma frequency band power up to 60 min after administration, whilst causing a decrease of power in delta, theta, alpha, and beta frequencies. Maximum cocaine levels measured from the dialysates appeared 30 min after dosing (300 nmol/l) and extracellular dopamine levels showed a peak concentration at 30 min and then returned to basal levels 120 min later.
In conclusion, these results indicate that cocaine induces an increase in dopaminergic transmission in the nucleus accumbens shell, and as expected, produces hyperactivity. The effect observed on the EEG frequency bands and in vivo microdialysis could serve as a physiological biomarker of target engagement studies and to set up a PK-PD relationship in drug discovery research.
Auditory steady-state responses (ASSR) provide a non-invasive technique to assess neural synchrony at a particular frequency. Attenuated phase-locking (PLI) of ASSRs in gamma frequency range is observed in schizophrenia and in animal models for psychosis [1]. State-sensitivity of 40 Hz ASSRs has been shown for schizophrenia, where PLIs increased with eyes closure in patients [2]. The effect of clozapine, which is prescribed in cases of treatment-resistant schizophrenia, on ASSR in humans is not clear. The aim of this study was to evaluate the effect of clozapine use on phase-locking of 40Hz ASSR and state-sensitivity in schizophrenia patients.
48 male patients with schizophrenia (according to ICD-10 criteria) were recruited from the in-patients of Republican Vilnius Psychiatric Hospital. Patients were divided into two groups: (1) resistant to standard antipsychotic medication and treated with clozapine (Cloz, n = 23); and (2) responsive to standard antipsychotic treatment (NCloz, n = 25). ASSRs to click stimuli at 40Hz were recorded using 9 channels in eyes open and eyes closed conditions, with 60 stimuli presented binaurally per condition. After conventional cleaning procedures, epochs of 700 ms were created starting at 100 ms prior to the stimulus onset and lasting for 600 ms post-stimulus. ASSRs were analyzed from Cz location, showing maximal activity. Mean phase-locking index (PLI) within 38-42Hz window was calculated for 100 ms bins and subjected to RM-ANOVA with time bin and task as within-subjects factors and group as a between-subjects factor.
Significant interaction of condition (eyes open vs eyes closed) and group (Cloz vs NCloz) factors (p = 0.038) was observed. This suggests that in Cloz group subjects tended to have lower PLIs in open eyes (p = 0.08), which increased with eyes closure (p < 0.001). In NCloz group, PLIs did not change with eyes closure (p > 0.05).
Our data propose that state-sensitivity of 40 Hz ASSRs vary depending on the treatment in patients with schizophrenia, subject receiving clozapine showing response increase with eyes closure in contrast to those on standard antipsychotic treatment.
Competing interests
The author declare that they have no competing interests
Research was supported by the grant MIP-009/2014 from Lithuanian Research Council.
References
1. O’Donnell BF, Vohs JL, Krishnan GP, Rass O, Hetrick WP, Morzorati SL. The auditory steady-state response (ASSR): a translational biomarker for schizophrenia. Suppl Clin Neurophysiol. 2013;62:101–12.
2. Griskova-Bulanova I, Dapsys K, Maciulis V, Arnfred SM. Closed eyes condition increases auditory brain responses in schizophrenia. Psychiatry Res Neuroimaging. 2013;211(2):183–5.
Background
The efficacy of rTMS in the treatment of major depressive disorder (MDD) has been well established in recent years. Most studies to date have employed the ‘5-cm’ rule for targeting stimulation of the Dorsolateral Prefrontal Cortex (DLPFC). New variations and improvements of this targeting technique include a ‘6-cm’ rule, the Beam-F3 method, and neuronavigated rTMS. Furthermore, it has been proposed that the efficacy of rTMS in MDD is more related to stimulating the area that is functionally connected to the subgenual anterior cingulate cortex (sgACC) rather than to specific cortical areas (Fox et al., 2012). Therefore, we set-out to develop and test a new method that employs knowledge about the functional role of the sgACC to establish in real time if the right cortical area is targeted.
Method
Several studies have shown that areas in the ventromedial prefrontal cortex are involved in parasympathetic regulation such as heart rate and respiration, and that neurostimulation of these areas led to heart rate decreases (Makovac et al., 2016), most likely through connectivity with the nervus vagus. Therefore, based on the notion that rTMS aims to transsynaptically stimulate the sgACC, we used electrocardiogram (ECG) R-peak triggered single pulse TMS to various frontal locations to establish the location that most consistently resulted in a lengthening of the R-R latency (reflective of a heart rate deceleration). This method of Neuro-Cardiac-Guided TMS or NCG TMS thus could be the equivalent of what the Motor Threshold is for the motor system, but then for the DLPFC with heart rate as an output.
Results
First preliminary results using a burst of 10 Hz TMS stimulation demonstrated that in a subject with a relatively large head circumference, no response was found at the ‘5 cm’ site (corresponding to FC4 in this subject), whereas the F4 location did result in a consistent heart rate deceleration. More data are currently being collected using a single pulse R-peak triggered approach and data will be presented. This method is pending for patent. Dutch Patent office: P100241NL00
Conclusions
In the treatment of MDD, Neuro-Cardiac-Guided TMS has the potential to become the equivalent of the ‘motor threshold’ for the DLPFC, and thereby would be a cost-effective and easy to use method for localizing the right stimulation target in the treatment of MDD, and also serve as a real-time control of adequate coil contact in patients undergoing rTMS treatment.
Background
Major depressive disorder (MDD) is a common and potentially lethal disorder affecting up to 14 % of all persons worldwide. However, 1/3 to 2/3 of patients are non-responders to first line therapy [1]. Even the electroconvulsive therapy (ECT) as the option of choice in therapy-resistant MDD still shows a high proportion of non-responders [2]. Due to the invasive nature of the ECT it would be desirable to know which subjects are likely to respond. In case of a predicted non-response to ECT, e.g. by means of electrophysiological electroencephalogram (EEG) parameters, other therapies of MDD (e.g. augmentation, polypharmacy etc.) could be chosen.
Methods
In this study, we retrospectively analysed two minute resting state EEG from patients with MDD who underwent ECT (4–12 sessions with 3/week) between 2005–2015 at the University Hospital of Zurich. Following several lines of evidence, we hypothesized altered non-linear connectivity in frontal networks including subgenual-, dorsolateral- and medio- prefrontal cortices being predictive for treatment outcome. Symptom severity and response/remission rates were assessed using the Global Clinical Impression (GCI) rating scale. Source estimates and connectivity measures were mapped using Low Resolution Brain Tomography (LORETA).
Results
Responders in comparison to non-responders showed a significant stronger non-linear connectivity in the frontal network within the EEG delta, alpha 1 and beta 1 frequency bands, while connectivity was weaker in theta, alpha 2, beta 2 and gamma frequency bands. Additionally, there were several non-significant correlations (from r = .15-.20) between symptom change and source estimates with e.g. a low midline theta-activity being associated with response to ECT.
Conclusions
Pre-treatment EEG-connectivity in frontal networks seems to have a predictive value for the efficacy of ECT treatment. Prospective trials and larger study groups are needed to further validate these markers and pave the way for possible usage in the clinical context.
Trial registration
Project ID: 2016–00562, Swissethics
No competing interests
References
1. Bromet E, Andrade LH, et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011 Jul 26;9:90. DOI:
10.1186/1741-7015-9-90
2. Dierckx B, Heijnen WT, et al. Efficacy of electroconvulsive therapy in bipolar versus unipolar major depression: a meta-analysis. Bipolar Disorders. 2012 Mar 14, Issue 2,146–150. DOI:
10.1111/j.1399-5618.2012.00997.x
Introduction
The present contribution deals with a particular study on animal model of psilocin-induced psychosis. QEEG methods addressing brain activity under certain set of conditions are usually based on bottom-up strategy preserving the low-level information e.g. coherence between two electrodes within particular frequency band at certain time after administration of a specific drug. Unfortunately, this approach leads to a combinatorial explosion if the effects of more drugs and their combinations are to be analyzed. This phenomenon makes data difficult to interpret. Here, we propose a way towards top-down strategy based on capturing an interpretable substance fingerprints. We show that unique functional brain clusters coherently modulated by a particular substance are embedded in multi-dimensional space of coherences and can be extracted by appropriate dimensional reduction technique [1].
Methods
The proposed technique takes coherences from 36 electrode pairs calculated in six discrete frequency bands (1-40Hz) at four specific time intervals (base line record, 20–30, 50–60, and 80–90 min post administration) and returns coherent topographic clusters. Our approach can be described in five following steps:
Coherence partial differences are calculated to extract functional changes between time intervals.
Coherence differences are processed by t-Distributed Stochastic Neighbor embedding (t-SNE) [2] to reduce data dimensionality on one hand and encode the original data structure on the other hand.
The silhouette clustering criterion is employed to determine a number of clusters in data [3]
The k-means algorithm categorizes data into clusters determined in step 2 and 3.
Obtained electrode pair clusters are visualized in topographic view.
Results
Psilocin clearly shows four functional clusters which are precisely symmetric in topographic view and which exhibit a global maximum of clustering criterion. In similar way, 5HT2A antagonist MDL-100907,and clozapine result in three clusters. This is in contrast with saline solution exhibiting no clustering and no global extremes of clustering criterion. Generally, all antagonists in combination with psilocin lead to less or no clusters.
Conclusions
The proposed technique is capable to contrast long term dynamics of coherences and find functional brain structures coherently modulated by a particular drug. This allows us to further study the mechanism behind the psilocin induced functional disconnection – the functional changes are specifically organized. All antagonists seem to compensate the psilocin induced organization. Our next step is to apply the technique in human psilocybin model of psychosis and search a new translation bridge between animal and human models.
This study was supported by project “National Institute of Mental Health (NIMH–CZ), number ED2.1.00/03.0078 and the grant AZV from MHCR no. 15-29370A.
I declare no conflict of interests.
References
1. Birjandtalab, J., Pouyan, M. B., & Nourani, M. (2016, February). Nonlinear dimension reduction for EEG-based epileptic seizure detection. In 2016 IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI) (pp. 595–598). IEEE.
2. Maaten, L. V. D., & Hinton, G. (2008). Visualizing data using t-SNE. Journal of Machine Learning Research, 9(Nov), 2579–2605.
3. Rousseeuw, P. J. (1987). Silhouettes: a graphical aid to the interpretation and validation of cluster analysis. Journal of computational and applied mathematics, 20, 53–65.
Background
Deviations in basic information processing, such as sensory gating, are thought to underlie cognitive deficits in schizophrenia. Treatment with the current first- and second-generation antipsychotics show almost no improvement in these early information processes. In parallel, there is little or no success in treating cognitive deficits with these drugs. In a recently conducted pilot-study from our laboratory we found that administering a single dose of clonidine, a noradrenergic α2A-receptor agonist, restored sensory gating in patients with schizophrenia to a level that no longer differed from an age and gender matched control group. It is expected that improvement of early information processing leads to improvement in cognition.
Goal
Improving currently available antipsychotic medication by normalizing early information processing.
Methods
Randomized Clinical Trial (RCT), conform to a randomized, balanced placebo-controlled design with two arms: in condition 1, patients (n = 25) will receive 6 weeks of additional clonidine treatment to their current medication, in condition 2, patients (n = 25) will receive 6 weeks of additional placebo treatment to their current medication. In addition, 25 age and gender matched healthy subjects will function as controls. Primary outcome is change in symptom severity, expressed as a change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of the 6-week treatment. Secondary outcomes are changes in cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia; BACS and Cambridge Neuropsychological Test Automated Battery; CANTAB), change in GAF (global assessment of functioning) scores and the measurement of various psychophysiological parameters of basic information processing, such as P50 suppression, prepulse inhibition of the startle reflex (PPI) and mismatch negativity (MMN).
Results
In line with our pilot-study it is expected that early information processing will improve. We predict that this will lead to an improvement in cognitive functioning after six weeks, which expectantly leads to lower symptom severity and a better quality of life.
Trial Registration
EudraCT Number: 2014-003008-53
Background
Autism Spectrum Disorder (ASD) often presents a treatment challenge due to the variety of symptoms that make each case unique. Medication prescribed to manage ASD associated symptoms such as anxiety, depression, attention issues, and behavioral problems often fail to alleviate symptoms and can produce undesirable side effects. The question is, why are the stimulants, selective serotonin reuptake inhibitors, and antipsychotics prescribed to alleviate these issues [1] effective in some patients but fail in others? The answer could be related to the increased prevalence of electroencephalographic abnormalities in psychiatric patients [2]. The presence of isolated epileptiform discharges (IEDs) may account for the treatment failure of these medications, especially antipsychotics, because these drugs lower seizure threshold, thus resulting in increased epileptiform activity. Electroencephalography (EEG) can be used to document the presence of IEDs that would otherwise go undetected. The purpose of the study was to reveal the prevalence of IEDs in the ASD patient population and to demonstrate the usefulness of the EEG for providing data to psychiatrists, neurologists, and developmental pediatricians to improve medication selection and outcomes for patients with ASD.
Method
The data was obtained from an Institution Review Board approved data archive from a multidisciplinary practice that treats a wide variety of refractory and neuroatypical patients. The study is comprised of 140 non-epileptic children, adolescents, and adults diagnosed with ASD, ages 4 to 25. A board certified electroencephalographer interpreted the EEGs in order to identify abnormalities.
Results
Of the 140 patients with ASD, 36.4 percent were found to have IEDs after an EEG screening. Chi-square analysis found no significant difference between genders among the three age groups. The findings indicate a high prevalence of IEDs among individuals with ASD.
Conclusion
Our results find that compared to the healthy population, a large number of patients with ASD have IEDs despite never having a seizure. The findings support the use of EEG in children, adolescents, and young adults with ASD, regardless of gender or age. This is particularly true for those who have failed prior medication attempts with stimulants, antidepressants, and/or antipsychotics. Utilizing the EEG for refractory cases in a psychiatric practice allows for more individualized and precise medication selection.
Consent to publish
This study does not contain details relating to individual participants.
Competing interests
The authors declare that they have no competing interests.
References
1. Oswald DP, Sonenklar NA. Medication use among children with autism spectrum disorders. J Child Adolesc Psychopharmacol. 2007;17(3):348–355. doi: 10.1089/cap.2006.17303.
2. Zimmerman EM, Konopka LM. Preliminary findings of single- and multifocused epileptiform discharges in nonepileptic psychiatric patients. Clin EEG Neurosci. 2014;45(4):285–292. doi: 10.1177/1550059413506001.
Background
A 61-year-old man with progressive myalgic encephalopathy/chronic fatigue syndrome was referred for neuromodulation. His condition, likely virally induced decades ago, was characterized by recurring periods of extreme fatigue, lasting months at a time. Severe fatigue had become unrelenting over the prior two years, impairing many dimensions of his life. Multiple immunological and neurological work-ups were negative and fibromyalgia had been ruled out. Patient failed many medically advised approaches, including antidepressants, acupuncture and a gluten-free diet.
Methods
Genetic analysis suggested he would respond to dopaminergic agents and to neuromodulation [1]. Trials of both amphetamines and methylphenidate ultimately failed but modafinil 200 mg did provide partial relief. Distance from the office precluded daily treatment with repetitive transcranial magnetic stimulation (rTMS). Transcranial direct current stimulation (tDCS) was chosen as a safe alternative feasible treatment [2], allowing cumulative, ongoing treatment to target ongoing inflammation. We used neurophysiological state markers of qEEG. Patient was trained with tDCS in the office and then treatment was self-applied at home daily with anode on left dorsal-lateral prefrontal cortex (LDLPFC), cathode on right (RDLPFC), 2 mA/min, 20 min, 40 mA total dose, using 1.5” diameter electrode pads. After four weeks, maintenance tDCS sessions were increased to twice daily (6 AM and 12 Noon) and modafinil was lowered to 100 mg.
Results
Follow-up qEEG testing was done one year after the initial qEEG when patient was in full recovery. Comparison of pre-treatment and post-treatment qEEG findings show minor improvement in excessive hypercoherent frontal alpha, a substantial 50 % drop in excess left temporal alpha, and a normalization at the very low end of the qEEG spectrum (less than 1 Hz). The patient noted: “[this treatment] has given me sustained relief from a chronic fatigue condition from which I’ve suffered throughout my adult life.”
Conclusions
Maintenance treatment with daily tDCS and modafinil likely exerted synergistic effects on the brain and immune system. The clinical recovery with notable improved sleep, energy, and ability to tolerate exercise are most likely to be reflected in slow wave oscillation changes. This case supports the need to look more closely at glial as well as neuronal impact, perhaps expanding qEEG to include slow wave markers. Clinicians are eager to have qEEG personalized biomarkers to optimize adjunctive tDCS stimulation in chronic psychiatric and neurological conditions, so often neuroinflammatory in nature [3].
Keywords
tDCS, myalgic encephalopathy, chronic fatigue syndrome, neuroinflammation, qEEG biomarker, personalized medicine
Consent to publish
Informed consent was obtained and the subject’s rights were protected.
Competing interests
No competing interests.
References
1. Oral A, Ilieva E, Küçükdeveci A, Varela E, Valero R, Verteanu M, Christodoulou N. Generalised and regional soft tissue pain syndromes. The role of physical and rehabilitation medicine physicians. The European perspective based on the best evidence. A paper by the UEMS-PRM Section Professional Practice Committee. Eur J Phys Rehabil Med. 2013; 49: 535–549.
2. Bikson M, Grossman P, Thomas C, Zannou A, Jiang, J, Adnan, et al., Safety of transcranial direct current stimulation: Evidence based update 2016. Brain Stim. 2016; 9: 641–661.
3. Yokoi Y, Sumiyoshi T. Application of transcranial direct current stimulation to psychiatric disorders: trends and perspectives. Neuropsychiatric Electrophysiology. 2015;1:10. doi: 10.1186/s40810-015-0012-x.
Introduction
Ketamine has been established as an alternative in the treatment of therapy-resistant major depressive disorder (MDD). Although response rates are reportedly high with up to 60-70 %, until now no biomarkers that could predict treatment response exist. As a first step, this case series aimed at identifying electrophysiological markers of arousal that reflect alterations of ongoing neuronal activity after treatment with ketamine.
Methods
Two patients (one 65-year-old female, one 78-year-old male) with therapy-resistant depression (> two treatment -approaches with SSRIs, SNRIs or TCAs) were treated with ketamine infusion four times respectively six times during three weeks. Resting state electroencephalogram (EEG) and electrocardiogram (ECG) were recorded at baseline and after treatment with four/six time ketamine infusion. Central nervous system (CNS) arousal was assessed using Vigilance Algorithm Leipzig (VIGALL). Autonomous nervous system (ANS) function was quantified using heart rate and heart rate variability measures (HRV). Changes of depressive symptoms were assessed using Hamilton Depression Rating Scale (HDRS).
Results
Both patients showed a marked decrease of depressive symptoms with a drop from 28 HDRS to 9 HDRS after four ketamine infusions and from 20 HDRS to 6 HDRS after six infusions respectively. In parallel, both patients showed a decrease of CNS arousal levels as assessed by VIGALL with increased amounts of low vigilance stages and decreased EEG-alpha peak frequencies after therapy in comparison to baseline EEG recording. Further, both patients revealed a lowered ANS arousal level as assessed by a reduction of heart rate >24 h after the last ketamine infusion in comparison to pretreatment condition.
Discussion
Following the arousal framework in MDD with a suggested high EEG-vigilance level in depression, the found decrease of CNS-arousal could be interpreted as a consequence of the anesthetic, i.e. vigilance decreasing effect of ketamine. In contrast, the decrease of heart rate remains elusive in the light of an initial increase of sympathetic function following infusion of ketamine. However, decrease of CNS- and ANS arousal level could lead to less pronounced MDD related behavioral aspects such as withdrawal and sleep disturbances. The predictive value of the EEG in ketamine treatment should be in the focus of further prospective randomized studies.
Consent to publish
Written informed consent has been obtained by all patients prior to publication.
Competing interests
The authors report no competing interests.
Caffeine and nicotine are the most consumed psychostimulants worldwide. Although the electrophysiological effects of each drug alone were studied extensively, the literature on the effects of their combined treatments on brain electrical activity is scarce. The present study aims to investigate the effects of the intraperitoneal injection of caffeine followed by the subcutaneous injection of nicotine after 1 h on electrical activity recorded from the cortex of rats (ECoG). It was found that the successive injection of caffeine and nicotine resulted in a significant increase in the power of delta frequency band but a significant decrease in the power of theta, beta-1 and beta-2. It was suggested that the caffeine and nicotine interaction could have an adverse effect by altering the cortical electrical activity that may indicate impair in memory encoding.
It has been demonstrated that after chiropractic spinal manipulation neural plastic changes occur in different areas of the brain. Different methods have been utilized to assess these changes, but the majority of the measurements to find the involved brain areas have been indirect. The objective of this study was to determine the changes in brain activity during tonic pain after single session of chiropractic care in a sub-clinical pain population by using source localization of the EEG.
Fifteen healthy volunteers (10 males, 32.1 ± 7.2 years) participated in two experimental sessions on separate days; chiropractic or control (sham) session in random order. The EEG was recorded continuously using a 61-channel system before and after either intervention during 72 s of cold pressor test at 2 °C (left hand). The pain and unpleasantness ratings were obtained on two separate numeric scales (range: 0 = no unpleasantness/pain to 10 = maximum unpleasantness/pain). The EEG was divided into 9 epochs (8 s each), which were separated into four frequency bands: delta (1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz) and beta (12–32 Hz). Subsequently, standardized low resolution brain electromagnetic tomography (sLORETA) was done on these frequency bands.
In the control experiment, the brain activity decreased in all frequency bands (all p ≤ 0.05), whereas no change in activity was seen after the chiropractic session (all p > 0.05). The decrease in activity in the control arm was specifically seen in the limbic (delta), frontal (theta) and temporal (alpha and beta) lobes The pain scores decreased in control arm (p < 0.05) whereas the unpleasantness scores decreased for both interventions (all p < 0.05).
The decrease in brain activity in the control arm reflects central habituation which occurs due to repetitive painful stimulation. The lack of this phenomenon in the chiropractic arm could imply that the chiropractic care normalizes the central nervous system leading to central dishabituation.
Introduction
To this date there are no standardized mapping methods that display animal cortical EEG on the brain surface. Therefore, this study describes a 3D imaging method to be used for EEG mapping on the surface of the rat brain. The aim of our study was to develop a software module and a standard for statistical brain mapping. Animal EEG data recorded during behavioral activity and inactivity served as a subject for analysis and brain mapping.
Methods
In this study we measured electrical activity of the rat brain. For imaging purpose, we used 3D brain model from atlas [1] and adjusted it for our own module. We confirmed the validity of the 3D brain model by comparing the dimensions of normalized brain scans of 9 rats of the Wistar strain typically used in our laboratories. We have created a MATLAB module for brain mapping with the use of the rat brain model and a possibility to place any number of electrodes on the surface of the rat brain. The spline interpolation was used for imaging activity on surface of the brain [2] and statistical brain-mapping was used to compare the two example behavioral conditions.
Results
The module was effectively used to display EEG activity on the 3D surface and to display the statistical group differences in the sample of the animal data between behavioral activity and inactivity. The module can also compare data from individual measurement with a group mean.
Conclusions
This study describes computation of splines interpolation curves that are important for the brain mapping in rats. This approach will be used for effective comparisons of brain activity of rats under various conditions and with variable number and placement of cortical electrodes.
This study was supported by the project Nr. LO1611 from the MEYS under the NPU I program, by project “National Institute of Mental Health (NIMH–CZ) (grant number ED2.1.00/03.0078 from the European Regional Development Fund), by Czech Technical University research program SGS (SGS15/229/OHK4/3 T/17), MH CZ – DRO („National Institute of Mental Health – NIMH) project nr.: 00023752 and PRVOUK34.
I declare no conflict of interests.
References
1. MAJKA, Piotr, Jakub M. KOWALSKI, Natalia CHLODZINSKA a Daniel K. WÓJCIK. 3D Brain Atlas Reconstructor Service—Online Repository of Three-Dimensional Models of Brain Structures. Neuroinformatics [online]. 2013, 11(4), 507–518 [cit. 2016-08-24]. DOI: 10.1007/s12021-013-9199-9. ISSN 15392791. Online: http://link.springer.com/10.1007/s12021-013-9199-9
2. PERRIN, F., J. PERNIER, O. BERTRAND a J.F. ECHALLIER. Spherical splines for scalp potential and current density mapping. Electroencephalography and Clinical Neurophysiology. 1989, 72(2), 184–187. DOI: 10.1016/0013-4694(89)90180-6. ISSN 00134694. Online: http://linkinghub.elsevier.com/retrieve/pii/0013469489901806
Background
Recent findings have suggested a relationship between abnormal γ-aminobutyric acid (GABA) function, disordered neuronal oscillations, and impaired executive function in schizophrenia. Additionally, there has been an increasing amount of interest in the therapeutic potential of these drugs in the treatment of this disorder. However, the neural oscillations that underlie the effects of GABA-modulating drugs on cognitive functioning require further work.
Objective
In an attempt to begin identifying which receptor subtypes may alter the neural oscillations underlying executive function via selective agonist actions, the study examined the effects of: a) a benzodiazepine drug with broad spectrum agonist actions at all GABA receptors containing the α1, α2, α3, and α5 subunits, and the γ subunit (in addition to the obligatory β subunit) and b) a drug with agonist actions at GABAB receptors. The objective of this pilot study was to examine the effects of single doses of these GABA enhancing drugs on resting state brain oscillations and executive function in healthy volunteers stratified by executive function performance.
Method
30 participants were assessed in a randomized, double-blind, placebo-controlled design. Three minutes of eyes closed resting state brain oscillations were measured from 8 electrode sites in response to an acute administration of lorazepam (Ativan®; 1.0 mg), a GABAA receptor positive allosteric modulator, and baclofen (Lioresal®; 10 mg), a GABAB receptor agonist. Executive function was assessed using the Groton Maze Learning Task (GMLT) of the CogState Schizophrenia Battery.
Results
Spectral analysis revealed overall reductions in alpha and theta oscillations with the lorazepam treatment. Follow-up analyses indicated that these reductions were in the better performing participants. Correlational analyses revealed that greater lorazepam-induced reductions in alpha and theta oscillations were associated with greater lorazepam-induced cognitive impairment. Reduced theta at placebo was also associated with worse performance. Additionally, smaller theta activity at placebo was associated with greater lorazepam-induced cognitive impairment.
Conclusion
The results suggest that GABAA-modulated alpha and theta oscillations are involved in the neural underpinnings of executive processing.
*These authors contributed equally
Scopolamine is a muscarinic acetylcholine receptor antagonist (mAChR) that induces cognitive impairments resembling those observed in Alzheimer’s disease (AD) and schizophrenia. It is used in drug development to demonstrate the reversal of the temporary scopolamine-induced cognitive deficits by a cognition enhancing compound. However, there is an urgent need for biomarkers that monitor therapeutic response; current biomarkers lack the desired accuracy, because of the large variability in healthy subjects and the often subtle disease-related changes. In EEG, pathophysiology is often expressed in multiple ways. Here we show that an integrative approach in which any biomarker that carries complementary information about a disease or therapeutic intervention can result in an accurate diagnostic index for better decision making in clinical trials.
Recently, we showed that EEG biomarker integration improves the prediction of conversion from mild cognitive impairment to Alzheimer’s disease (AD) compared with a single-biomarker based prediction [1]. The integrative biomarker index can be used for stratification of patients at recruitment in clinical studies and for documenting and quantifying effects of intervention. Here, we provide additional proof-of-concept that EEG-based prediction can be improved with the integrative biomarker approach in clinical trials where a drug is tested in a scopolamine challenge model in healthy subjects.
For this purpose, we have developed an integrative EEG-biomarker index (mAChR index) that is optimally sensitive to the CNS effects of scopolamine, to objectively determine whether reversal of scopolamine effects by a cholinergic compound is successful. The mAChR index yielded higher classification performance than any individual EEG biomarker with accuracy, sensitivity, specificity and precision ranging from 88–92 %. This significantly outperforms the single-best EEG biomarker (relative delta power). Validation on an independent dataset indicated the robustness of the index. To support the validity of scopolamine as a model for AD pathophysiology, we show that the mAChR index discriminates healthy elderly from patients with AD.
We address this by using novel features of the Neurophysiological Biomarker Toolbox (http://www.nbtwiki.net/), which employ data-mining algorithms to combine the information from multiple biomarkers. Our results demonstrate that integrating information from multiple EEG biomarkers can enhance the accuracy of identifying disease or drug intervention, which should be of interest to a wide range of clinical trials.
References
1. Poil SS, de Haan W, van der Flier WM, Mansvelder HD, Scheltens P, Linkenkaer-Hansen K. Integrative EEG biomarkers predict progression to Alzheimer’s disease at the MCI stage. Front Aging Neurosci. 2013; 5:58.
Our motivations influence our actions in predictable ways. The promise of a reward promotes behavioural activation, while the threat of a punishment context promotes inhibition. However, these motivational biases can at times be at odds with our goals. At such times, we need to be able to suppress them, which has been suggested to be implemented by the midfrontal cortex. We developed a novel paradigm and computational models of behavior to disentangle the impact of such motivational response biases, from the impact of learning from reward and punishment outcomes. Participants (N = 34) completed this task while recording surface EEG. As expected, cue valence strongly biased action. Midfrontal theta-band oscillatory activity was increased in those trials, where the motivational response bias conflicted with the required response, particularly when subjects successfully suppressed the motivational bias. We will present further analyses to dissociate the role of midfrontal cortex in learning from reward and punishment outcomes. This work will allow us to characterize how motivations drive biases in both choice and learning, and how we may learn to suppress these when they are at odds with our instrumental goals. This work has relevant implications for a range of psychiatric disorders associated with a maladaptive reliance on impulsive, motivation-driven responding including addiction, impulse control and ADHD.
Sharp wave ripples (SPW-Rs) represent the most synchronous population patterns observed in the mammalian brain and are considered a cognitive biomarker for episodic memory and planning. SPW-Rs occur during several off-line states of the brain including non-REM sleep; are modulated by many neurotransmitter systems; and affect both cortical and subcortical structures by their excitatory output. Selective disruption of SPW-Rs impairs memory formation and pathological SPW-Rs have been observed in rodent models for neurodegenerative diseases. Quantification of these synchronous population patterns associated with memory processes is instrumental for a better comprehension of neurodegenerative diseases as well as for assessing the efficacy of novel pharmacological treatments. The purpose of this study was twofold: first, to develop and validate a novel computer-automated touchscreen-based spatial search task assessing either working memory or memory consolidation in Long-Evans rats; second, to quantify SPW-Rs’ activity in this spatial search task during working memory or memory consolidation combined with pharmacological glutamatergic and cholinergic modulation. For the working memory component of the task, rats had to find a hidden location on the touchscreen with either a short (2 s) or long (10 s) delay between 10 consecutive trials with each delay having 4 different locations presented within one session. During these delays; hippocampal SPW-Rs from the CA1 stratum pyramidal cell layer were measured following each completed trial, using implanted 4-shank silicon electrodes. Here, SPW-Rs were measured when the rat was moving at speeds of less than 4 cm/s, by use of video monitoring to ensure events analyzed were associated with quiescent periods only. Results indicate that Scopolamine 0.1 mg/kg but not 0.05 mg/kg decreased performance for the long but not for the short delay. For the memory consolidation component of the task, rats received 1-day or 4-day acquisition session/s of a single hidden location with variable encoding strength using few (<10) or many (>40) trials per session. Memory consolidation of the location was measured 24 h after acquisition by the use of a probe trial. SPW-Rs were measured when the rats were asleep both before and after the acquisition session. A differential effect on encoding versus consolidation was addressed using pharmacological manipulation of glutamatergic and cholinergic systems. This study reinforces the strength of combining neurophysiological and cognitive behavioral assessment to further understand memory processes and effects of pharmacological treatments thereon.
Targeting the N-methyl-D-aspartate-receptor (NMDAR) is a major approach for treating negative symptoms of schizophrenia. The ketamine model of schizophrenia has the advantage of comprehensively producing schizophrenia like symptoms such as positive, cognitive and negative symptoms in healthy volunteers. The amplitude of the Mismatch Negativity (MMN), a neurophysiological parameter related to infrequent stimuli, is known to be significantly reduced in schizophrenic patients but also in healthy controls receiving ketamine [1, 2]. Accordingly, it was the aim of the present study to investigate whether changes of MMN during ketamine administration are related to the emergence of negative symptoms in healthy subjects.
Therefore, we examined the impact of ketamine on MMN amplitudes and its sources (sources localization approach: low resolution electromagnetic tomography (LORETA)) by means of 64-channel electroencephalography (EEG) recording during performance of an auditory MMN paradigm and assessed the psychopathological status using the Altered State of Consciousness (5D-ASC) Rating Scale and the Positive and Negative Syndrome Scale (PANSS). Twenty-four male, healthy volunteers were measured with pharmacological EEG using a single-blind, randomized, placebo-controlled crossover design.
We identified significant changes of the MMN response, to both duration and frequency deviants, under ketamine condition as well as a significant increase in all PANSS scores. Reductions of MMN amplitudes were significantly correlated with more pronounced negative symptoms, assessed by the PANSS.
Accordingly, the MMN might represent a biomarker for negative symptoms in schizophrenia related to an insufficient NMDAR system and could be used to identify schizophrenia patients with negative symptoms due to NMDAR dysfunction and thus to determine a maximal benefit of drugs modulating neurotransmission at the NMDAR.
Competing interests
The authors declare that they have no competing interests.
References
1. Shelley AM, Ward PB, Catts SV, Michie PT, Andrews S, McConaghy N. Mismatch negativity: an index of a preattentive processing deficit in schizophrenia. Biol Psychiatry. 1991; 30(10):1059–1062.
2. Umbricht D, Koller R, Vollenweider FX, Schmid L. Mismatch negativity predicts psychotic experiences induced by NMDA receptor antagonist in healthy volunteers. Biol Psychiatry. 2002; 51(5):400–406.
Introduction
The serotonergic hallucinogen psilocybin and its active metabolite psilocin nowadays receive a lot of attention in the scientific community as a research tool for modeling psychosis. First experiments assessing brain activity after psilocybin administration in humans using PET and fMRI found contradictory results [1,2]. More recently, a study directly measuring neuronal activity using MEG confirmed massive inhibition of brain activity [3]. The aim of our animal study was to assess psilocin-induced changes in quantitative EEG (QEEG) in rats in order to explore the role of different serotonergic receptors in psilocin action.
Methods
The substances used were: psilocin (4 mg/kg s.c.), 5HT1A antagonist WAY 100635 maleate (1 mg/kg s.c.), 5HT2A antagonist MDL-100907 tartarate (0.5 mg/kg s.c.), 5HT2C antagonist SB-242084 (1 mg/kg s.c.), haloperidol 0.1 mg/kg s.c. and clozapine 5 mg/kg i.p. For EEG experiments, rats were stereotactically implanted with 12 active electrodes onto the surface of the cortex under isoflurane anesthesia. EEG was recorded in freely moving rats after one-week recovery from surgery. EEG power spectra (local synchronization) and coherence (long projections) were subsequently analyzed comparing the drugs’ effect in time (20–30, 50–60 and 80–90 min post administration) to the baseline record. To avoid moving artifacts and effects of behavior on EEG, only EEG traces corresponding to behavioral inactivity were included in the analysis.
Results
Psilocin generally decreased both EEG absolute spectral power and EEG coherences. The changes in spectral power induced by psilocin were normalized partially by all substances used, mainly in the lower frequency bands. However, only 5HT1A and 5HT2A antagonists partially normalized the psilocin-induced decrease of EEG coherences. The specific QEEG pattern of each substance and the temporal dynamics of QEEG changes will be presented.
Conclusions
Psilocin-induced changes in QEEG in rats are very similar to our recent human data with psilocybin and are in accordance with the concept of psychosis as a disconnection syndrome. All the specific 5HT antagonists and both antipsychotic drugs specifically affected the EEG spectral power induced by psilocin. Surprisingly, only 5HT1A and 5HT2A antagonists were able to partially reverse psilocin-induced disconnection. These results indicate that 5HT1A and 5HT2A receptors might be involved in the increase of entropic brain activity during psychedelic state as well as acute psychosis.
This study was supported by the grant IGA MHCR NT/13897, by Charles University research program PRVOUK P34, by project “National Institute of Mental Health (NIMH–CZ)”, grant number ED2.1.00/03.0078, and by the European Regional Development Fund.
I declare no conflict of interests.
References
1. Vollenweider F.X., Leenders K.L, Scharfetter C., Maquire P., Stadelmann O., Angst J., 1997. Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacol, 16(5):357–372.
2. Carhart-Harris R.L., Erritzoe D., Williams T., Stone J.M., Reed L.J., Colasanti A., Tyacke R.J., Leech R., Malizia A.L., Murphy K., Hobden P., Evans J., Feilding A., Wise R.G., Nutt D.J., 2012. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci USA, 109(6):2138–2143.
3. Muthukumaraswamy S.D., Carhart-Harris R.L., Moran R.J., Brookes M.J., Williams T.M., Errtizoe D., Sessa B., Papadopoulos A., Bolstridge M., Singh K.D., Feilding A., Friston K.J., Nutt D.J., 2013. Broadband cortical desynchronization underlies the human psychedelic state. J Neurosci, 33(38):15171–15183.
The serotonergic 5-HT2C receptor is a key contributor to a variety of medical conditions including psychiatric and neurological diseases. The development of therapeutic approaches at this receptor, with both, agonists and antagonists continues to be in focus [1]. Using a novel wireless EEG device (Neural Activity Tracker-1) and a novel in-house developed statistical algorithm we investigated electrophysiological changes in sleep structure and EEG power spectral distribution caused by the highly selective 5-HT2C receptor agonist CP-809,101.
In two independent studies, male Fischer rats with chronically implanted supracortical EEG-electrodes were treated with 10 mg/kg of CP-809,101. In the 1st study, sleep structure changes in terms of total sleep time, percent of time spent in different vigilance states, the number of rapid eye movement (REM) episodes, and latency to first sleep and REM episode were analyzed. Treatment with CP-809,101 led to attenuation of time spent in mild, deep, and REM sleep. It increased time spent in wake state and latency to first sleep and first REM episode.
The 2nd study investigated power spectral distribution changes. A refined statistical method of baseline-adjusted power spectral changes revealed an attenuation of delta and theta band by CP-809,101 in comparison to vehicle recordings while maintaining the delta/theta ratio. Our results clearly demonstrate that acute treatment with CP-809,101 changes both sleep architecture and power spectral parameters in Fischer rats.
5-HT2C agonists have been suggested to exhibit antidepressant-like profile that fits to the sleep changes observed in our study. Further, 5-HT2C agonists have been reported to inhibit theta oscillation, desynchronizing the EEG and leading to shifts to lower frequencies [2,3]. Yet, despite the inhibition of theta oscillation and desynchronization of the EEG by CP-809,101, the ratio between delta/theta revealed no changes underlying the wake-promoting effects of CP-809,101.
Disclosures
All authors are employees of AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
References
1. Cunningham, K. A., Fox, R. G., Anastasio, N. C., Bubar, M. J., Stutz, S. J., Moeller, F. G., … & Rosenzweig-Lipson, S. (2011). Selective serotonin 5-HT 2C receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine-vs. sucrose-associated cues. Neuropharmacology, 61(3), 513–523.
2. Hajós, M., Hoffmann, W. E., & Weaver, R. J. (2003). Regulation of septo-hippocampal activity by 5-hydroxytryptamine2C receptors. Journal of Pharmacology and Experimental Therapeutics, 306(2), 605–615.
3. Sörman, E., Wang, D., Hajos, M., & Kocsis, B. (2011). Control of hippocampal theta rhythm by serotonin: role of 5-HT2c receptors. Neuropharmacology, 61(3), 489–494.
Background
P300 (P3) is an index of focal attention processes and memory updating. Impaired cognition is one of hallmark features of psychotic disorders. Both psilocybin (5-HT2A agonist) and cannabinoids induce acute transient psychotic symptoms and have previously been used as putative models for psychosis. In order to investigate the extent of cognitive disruption during psilocybin and cannabis intoxication, information processing was evaluated by means of both sensory event related potentials (P2, N2) and cognitive potential P3.
Methods
Data from two separate studies are presented.
1) In a placebo-controlled design, 20 healthy adults were administered a dose of psilocybin per os (0,26 mg/kg) and placebo during 2 separate sessions.
2) In an ecologically valid model of cannabis intoxication, 34 recreational users, 32 chronic users and 30 healthy age- and gender-matched cannabis non-users were recruited. ERPs were recorded in a sound-attenuated room with each participant lying down with their eyes closed in a comfortable setting with two sitters (male and female) being present for the whole time. An oddball paradigm with 120 frequent and 30 target tones presented binaurally in a pseudo-random order was used. Data were acquired with a standard 32-channel digital EEG amplifier BrainScope (unimedis, Prague) with 20 active scalp electrodes and oculogram according to the 10/20 system.
Results
Psilocybin: A repeated-measures ANOVA on latencies and amplitudes of P2, N2 and P3 revealed significant effect of psilocybin only on P3 amplitude. Further analysis showed correlations between P3 amplitude and selected variables from objective and subjective rating scales. Cannabis: While the groups did not differ in P3 latency or amplitude, ANOVA revealed a main effect of group for P2 component with recreational users displaying smaller amplitudes than healthy controls. Furthermore, N2 latency in recreational users was shorter when compared to healthy controls.
Conclusion
In line with previous findings, psilocybin induced abnormalities in higher-order cognition. Impaired processing is likely to be related to heightened activity of the serotonergic system at the peak of psilocybin intoxication. Although P2 findings in cannabis model indicate attention difficulties, non-significant P3 results need to be considered as well and are discussed in light of the ecological validity of the model.
This study was supported by the grant IGA MHCR NT/13897, by Charles University research program PRVOUK P34, by project “National Institute of Mental Health (NIMH–CZ)”, grant number ED2.1.00/03.0078, and by the European Regional Development Fund.
I declare no conflict of interests.
In major depressive disorder (MDD) research, frontal alpha asymmetry (FAA) has frequently been reported as a potential discriminator between depressed and healthy individuals, although contradicting studies and non-significant results have been published [1, 2]. Locating an MDD biomarker could benefit many people, as MDD is predicted by the WHO to become the second most debilitating disease by 2020. The aim of the current meta-analysis is to clarify the relationships between MDD and FAA further, through analyzing new research from the last decade and put it in perspective by comparing current and past findings (for example a meta-analysis [1]).
Cohen’s d will be calculated from the means and standard deviations for FAA measures (subtracting mean log transformed left midfrontal alpha from mean log transformed right midfrontal alpha [ln(F4)-ln(F3)]), or a similar measure. Possible covariates including age, gender, handedness, year of publication, country of residence, depression severity, medication, EEG recording length, keeping eyes either open, closed or both, EEG reference, and used alpha frequency will be explored. A study will be included if the article (1) reports on both depressed and healthy individuals, (2) provides an FAA measure involving F3 and F4, and (3) provides all data regarding above mentioned covariates (reported either directly or obtained through contact with corresponding authors).
Preliminary results of our currently ongoing meta-analysis will be presented. On the one hand, previous studies have reported relative more left-sided alpha in MDD (sometimes only for higher frequency alpha and not for every EEG montage). On the other hand, non-significant and even opposite results have been reported, showing no baseline FAA differences between depressed patients and controls, or finding relatively more right-sided frontal alpha. Our expectation is that there will be no difference in FAA between MDD and non-MDD groups, based on more recent studies reporting contradicting results, as well as today’s largest investigated sample regarding this topic, the iSPOT-D study [2], showing non-significant results. If non-significance is indeed demonstrated, the use of FAA as a diagnostic tool can be questioned. Nevertheless, its contribution to other applications (such as treatment prediction) could be further explored.
References
1. Thibodeau R, Jorgensen R, Kim S. Depression, Anxiety, and Resting Frontal EEG Asymmetry: A Meta-Analytic Review. J Abnorm Psychol. 2006; 115;715–729.
2. Arns M, Bruder G, Hegerl U, Spooner C, Palmer D, Etkin A, Fallahpour K, Gatt J, Hirshberg L, Gordon E. EEG alpha asymmetry as a gender-specific predictor of outcome to acute treatment with different antidepressant medications in the randomized iSPOT-D study. Clin Neurophysiol. 2016; 127:509–519.
Patients suffering from schizophrenia have been shown to exhibit impaired P50 ERP amplitude-reduction to the second (S2) relative to the first (S1) of identical brief auditory stimuli. This reduction is often mentioned in connection with the inability to filter redundant sensory stimuli typically manifested as inability to gate neuronal responses related to the P50 wave [1, 2]. The key neuronal structure responsible for the sensory gating process is the hippocampus. Inhibition of redundant stimuli in the hippocampus is affected via the release of glutamate from excitatory pathways, which is controlled by GABAB receptors. It is closely connected with a physiological deficit of hippocampal GABAergic interneurons, which demonstrates neuropathological changes in schizophrenia. Several drugs are able to improve sensory gating, the effect of which is explained by their ability to disinhibit GABAergic neurons in the hippocampus. The effect of setrons may be an example of such effective gabaergic interneurons disinhibition. This antagonist of 5-HT 3 receptors increased (by disinhibition of gabaergic interneurons) release of acetylcholine, which by agonism of alpha7 nicotinic receptors improved auditory gating [3]. Besides the hippocampus the prefrontal cortex is an important neuronal part of the sensory gating. Patients with a prefrontal damage fail to suppress irrelevant sensory information, which leads to increased neural noise and inability to inhibit task-irrelevant information during behavioral tasks requiring performance over a delay. Some of the P50 source analysis leads to the conclusion that while the temporal cortices are the main generator of the P50 component, the prefrontal cortex seems to be a main contributor to the process of sensory gating (P50 amplitude reduction) [4]. As in the case of the hippocampus, there are drugs that improve sensory gating by acting on the prefrontal cortex. Clonidine acts as an agonist of α2A noradrenergic receptors and has a proven restorative effect on sensory gating. Stimulation of α2A noradrenergic receptors on PFC spines by clonidine leads to strengthening of network connectivity, increase in neuronal PFC firing, and thus improves PFC regulation of sensory gating [5]. The aim of our poster is to interlink a pharmacological profile of neuronal areas that are involved in the inhibition of P50 wave with clinical treatment of schizophrenia. We believe that the neuropharmacological aspects of P50 wave offer an interesting hypothesis relating mainly to the pharmacological augmentation strategies. Some of them are suggested and explained further in our poster communication.
This work was supported by the project „National Institute of Mental Health (NIMH-CZ)“, under grant number ED2.1.00/03.0078, the European Regional Development Fund, the Charles University research program PRVOUK P34, and the travel grant of the Czech neuropsychopharmacological society.
References
1. Dalecki A, Green AE, Johnstone SJ, Croft RJ. The relevance of attention in schizophrenia P50 paired stimulus studies. Clin Neurophysiol. 2016 Jun;127(6):2448–54.
2. Vlcek P, Bob P, Raboch J. Sensory disturbances, inhibitory deficits, and the P50 wave in schizophrenia. Neuropsychiatr Dis Treat. 2014;10:1309–15.
3. Freedman R, Adler LE, Myles-Worsley M, Nagamoto HT, Miller C, Kisley M, et al. Inhibitory gating of an evoked response to repeated auditory stimuli in schizophrenic and normal subjects. Human recordings, computer simulation, and an animal model. Arch Gen Psychiatry. 1996 Dec;53(12):1114–21.
4. Knight RT, Staines WR, Swick D, Chao LL. Prefrontal cortex regulates inhibition and excitation in distributed neural networks. Acta Psychol (Amst). 1999 Apr;101(2–3):159–78.
5. Arnsten AF, Jin LE. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J Biol Med. 2012 Mar;85(1):45–58.
Background
Previous research suggests that high exposure to solar irradiation has a preventive effect on the development of attention-deficit/hyperactivity disorder (ADHD) [1]. Note that the Dopaminergic DRD4 receptor is involved in phototransduction in the retina. Interestingly, being a DRD4 7R carrier while being born in spring and summer has been demonstrated to result in a 2.8 higher likelihood of developing hyperkinetic disorder, equivalent to ADHD [2]. These findings suggested a possible gene X environment interaction between the DRD4 7R allele and season of birth. The current study focused on the influence of solar irradiation exposure around birth on adult attentional performance.
Methods
We used an RDoC approach focusing on “inattention” operationalized as false negative errors, i.e. missed targets, from two cognitive tasks; the auditory oddball task and the continuous performance task. DRD4 genotype was regarded a vulnerability to develop ADHD, i.e. high inattention. We specifically aimed to test hypotheses that we generated based on previous studies. We distinguished the solar irradiation at birth-month from the difference in the solar irradiation between the month after birth and the month of birth to further understand previous results. Data of 277 healthy adult participants were extracted from the Brain Resource International Database. This database contains data from multiple laboratories (New York, Rhode Island, Nijmegen, Sydney, and Adelaide) creating variability in solar irradiation data.
Results
Results showed an interaction between DRD4 genotype and transition in solar irradiation following birth on the number of inattention errors made (F(1, 269) = 6.785, p = .010). More specifically, a one-way ANOVA for the DRD4 7R carrier group showed a significant difference between positive and negative transition in solar irradiation (1,86) = 8.602, p = .004, d = −0.449), while data from participants lacking the DRD4 7R genotype did not differ.
Conclusions
These results provide evidence that factors around birth influence adult performance and may strengthen or weaken the risk to develop attention related problems once already genetically at risk. Results also further strengthen the hypothesis that a relationship between solar irradiation and ADHD exists, possibly mediated by the dopamine DRD4 receptor.
References
1. Arns, M., van der Heijden K.B., Arnold L.E., Kenemans J.L. Geographic variation in the prevalence of attention-deficit/hyperactivity disorder: the sunny perspective. Biol psychiat. 2013 Oct 15;74(8):585–90.
2. Seeger, G., Schloss, P., Schmidt, M.H., Rüter-Jungfleisch, A., Henn, F.A. (2004). Gene-environment interaction in hyperkinetic conduct disorder (HD + CD) as indicated by season of birth variations in dopamine receptor (DRD4) gene polymorphism. Neuroscience Letters, 366, 282–286.
Background and aim
Prospective studies have linked sucrose consumption to weight gain and obesity, which are in turn associated with the development of a range of adverse health effects including diabetes and premature cardiovascular disease, both identified as leading causes of health loss in New Zealand and Europe. Recent work has also reported that there are cognitive deficits induced by elevated intake of sugars. There is the need to improve understanding of how the processes involved in the deterioration of cognitive functions and mechanisms are modulated by the sucrose. The present study was to investigate the effect of sucrose on resting EEG alpha asymmetry using EEG.
Methods
We recorded resting, spontaneous EEG from 64 scalp electrodes according to the international 10/20 system (NeuroScan, A/D rate: 1000 Hz) while healthy volunteers (N = 10) were orally administered sucrose (with 1 % sweetness) and placebo solutions. The participants held these solutions in their mouth, still with eyes closed. EEG spectral indices from the left and right frontal (F3, F4), central (C4, C3) and posterior regions (P4, P3) of the scalp were extracted by a continuous wavelet transform and normalised into spectral distribution in the alpha (8–12 Hz) band. Sucrose-induced change in alpha asymmetry was analysed using ANOVA, with conditions (sucrose, placebo), hemisphere (left, right) and regions (frontal, central and posterior) as the within-subjects factors.
Results
Our results showed that there was no significant condition* hemisphere effect. However, a medium effect size (r = 0.33) may indicate some effect which did not turn out to be significant due to the limited sample size. A tendency for a reduced asymmetry value (i.e. F4-F3) was observed when the group was exposed to sucrose.
Discussion
Our findings provide preliminary evidence of sucrose-induced change in brain activity.
