Opposite Modulation of the NMDA Receptor by Glycine and S-Ketamine and the Effects on Resting State EEG Gamma Activity: New Insights into the Glutamate Hypothesis of Schizophrenia.

NMDA-receptor hypofunction is increasingly considered to be an important pathomechanism in schizophrenia. However, to date, it has not been possible to identify patients with relevant NMDA-receptor hypofunction who would respond to glutamatergic treatments. Preclinical models, such as the ketamine model, could help identify biomarkers related to NMDA-receptor function that respond to glutamatergic modulation, for example, via activation of the glycine-binding site. We, therefore, aimed to investigate the effects of opposing modulation of the NMDA receptor on gamma activity (30-100 Hz) at rest, the genesis of which appears to be highly dependent on NMDA receptors. The effects of subanesthetic doses of S-ketamine and pretreatment with glycine on gamma activity at rest were examined in twenty-five healthy male participants using 64-channel electroencephalography. Psychometric scores were assessed using the PANSS and the 5D-ASC. While S-ketamine significantly increased psychometric scores and gamma activity at the scalp and in the source space, pretreatment with glycine did not significantly attenuate any of these effects when controlled for multiple comparisons. Our results question whether increased gamma activity at rest constitutes a suitable biomarker for the target engagement of glutamatergic drugs in the preclinical ketamine model. They might further point to a differential role of NMDA receptors in gamma activity generation.

Glycine attenuates impairments of stimulus-evoked gamma oscillations in the ketamine model of schizophrenia.

Although a substantial number of studies suggests some clinical benefit concerning negative symptoms in schizophrenia through the modulation of NMDA-receptor function, none of these approaches achieved clinical approval. Given the large body of evidence concerning glutamatergic dysfunction in a subgroup of patients, biomarkers to identify those with a relevant clinical benefit through glutamatergic modulation are urgently needed. A similar reduction of the early auditory evoked gamma-band response (aeGBR) as found in schizophrenia patients can be observed in healthy subjects following the application of an NMDA-receptor antagonist in the ketamine-model, which addresses the excitation / inhibition (E/I) imbalance of the disease. Moreover, this oscillatory change can be related to the emergence of negative symptoms. Accordingly, this study investigated whether glycine-related increases of the aeGBR, through NMDA-receptor co-agonism, accompany an improvement concerning negative symptoms in the ketamine-model. The impact of subanesthetic ketamine doses and the pretreatment with glycine was examined in twenty-four healthy male participants while performing a cognitively demanding aeGBR paradigm with 64-channel electroencephalography. Negative Symptoms were assessed through the PANSS. S-Ketamine alone caused a reduction of the aeGBR amplitude associated with more pronounced negative symptoms compared to placebo. Pretreatment with glycine attenuated both, the ketamine-induced alterations of the aeGBR amplitude and the increased PANSS negative scores in glycine-responders, classified based on relative aeGBR increase. Thus, we propose that the aeGBR represents a possible biomarker for negative symptoms in schizophrenia related to insufficient glutamatergic neurotransmission. This would allow to identify patients with negative symptoms, who might benefit from glutamatergic treatment.

Ketamine Alters Functional Gamma and Theta Resting-State Connectivity in Healthy Humans: Implications for Schizophrenia Treatment Targeting the Glutamate System.

Disturbed functional connectivity is assumed to cause neurocognitive deficits in patients suffering from schizophrenia. A Glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction has been suggested as a possible mechanism underlying altered connectivity in schizophrenia, especially in the gamma- and theta-frequency range. The present study aimed to investigate the effects of the NMDAR-antagonist ketamine on resting-state power, functional connectivity, and schizophrenia-like psychopathological changes in healthy volunteers. In a placebo-controlled crossover design, 25 healthy subjects were recorded using resting-state 64-channel-electroencephalography (EEG) (eyes closed). The imaginary coherence-based Multivariate Interaction Measure (MIM) was used to measure gamma and theta connectivity across 80 cortical regions. The network-based statistic was applied to identify involved networks under ketamine. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). Ketamine caused an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01). Significant increases in resting-state gamma and theta power were observed under ketamine compared to placebo (p < 0.05). The source-space analysis revealed two distinct networks with an increased mean functional gamma- or theta-band connectivity during the ketamine session. The gamma-network consisted of midline regions, the cuneus, the precuneus, and the bilateral posterior cingulate cortices, while the theta-band network involved the Heschl gyrus, midline regions, the insula, and the middle cingulate cortex. The current source density (CSD) within the gamma-band correlated negatively with the PANSS negative symptom score, and the activity within the gamma-band network correlated negatively with the subjective changed meaning of percepts subscale of the 5D-ASC. These results are in line with resting-state patterns seen in people who have schizophrenia and argue for a crucial role of the glutamate system in mediating dysfunctional gamma- and theta-band-connectivity in schizophrenia. Resting-state networks could serve as biomarkers for the response to glutamatergic drugs or drug development efforts within the glutamate system.

Alterations of oscillatory neuronal activity during reward processing in schizophrenia.

OBJECTIVES: Reward system dysfunctions are considered to be a pathophysiological mechanism in schizophrenia. Electrophysiological studies of reward system functions have identified frequency-specific brain networks for the processing of positive (high-beta frequency) and negative (theta frequency) events. Remarkably, midbrain dopaminergic signalling also includes theta and high-beta frequency modes, which have been assumed to reflect tonic and phasic dopamine responses, respectively. The aim of the present study was to identify alterations of oscillatory responses to reward feedback in patients with schizophrenia. METHODS: Seventeen patients with schizophrenia and 18 healthy controls performed a gambling task during recording of 64-channel electroencephalography. The theta and high-beta band total power were investigated in response to feedback events depending on feedback valence (loss or gain) and magnitude (5 vs. 25 points). RESULTS: Both the increase of theta oscillatory activity in response to loss feedback (compared to gain feedback) and the increase of high-beta oscillatory activity in response to gain feedback (compared to loss feedback) were reduced in patients. The difference in high-beta responses to gain versus loss feedback in patients was associated with the severity of negative symptoms. CONCLUSIONS: Our findings are consistent with current models of reward system dysfunction in schizophrenia, and indicate deficits in both cortical tonic and subcortical phasic dopamine activity, consistent with the complex dopaminergic abnormalities in schizophrenia.

Reduced auditory evoked gamma-band response and schizophrenia-like clinical symptoms under subanesthetic ketamine.

Abnormal gamma-band oscillations (GBO) have been frequently associated with the pathophysiology of schizophrenia. GBO are modulated by glutamate, a neurotransmitter, which is continuously discussed to shape the complex symptom spectrum in schizophrenia. The current study examined the effects of ketamine, a glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist, on the auditory-evoked gamma-band response (aeGBR) and psychopathological outcomes in healthy volunteers to investigate neuronal mechanisms of psychotic behavior. In a placebo-controlled, randomized crossover design, the aeGBR power, phase-locking factor (PLF) during a choice reaction task, the Positive and Negative Syndrome Scale (PANSS) and the Altered State of Consciousness (5D-ASC) Rating Scale were assessed in 25 healthy subjects. Ketamine was applied in a subanaesthetic dose. Low-resolution brain electromagnetic tomography was used for EEG source localization. Significant reductions of the aeGBR power and PLF were identified under ketamine administration compared to placebo (p < 0.01). Source-space analysis of aeGBR generators revealed significantly reduced current source density (CSD) within the anterior cingulate cortex during ketamine administration. Ketamine induced an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01) and increased response times (p < 0.001) and error rates (p < 0.01). Only negative symptoms were significantly associated with an aeGBR power decrease (p = 0.033) as revealed by multiple linear regression. These findings argue for a substantial role of the glutamate system in the mediation of dysfunctional gamma band responses and negative symptomatology of schizophrenia and are compatible with the NMDAR hypofunction hypothesis of schizophrenia.

Impact of physical or sexual childhood abuse on plasma DHEA, DHEA-S and cortisol in a low-dose dexamethasone suppression test and on cardiovascular risk parameters in adult patients with major depression or anxiety disorders.

While the impact of childhood trauma on basal and dynamic cortisol regulation has widely been studied, the most abundant steroid hormones dehydroepiandrosterone (DHEA) and its sulphated derivative DHEA-S have received little attention in this context. One-hundred in-door patients suffering from major depression or an anxiety disorder filled in the Childhood Trauma Questionaire. A low dose dexamethasone suppression test (DST) measuring DHEA, DHEA-S and cortisol was performed. Furthermore, various cardiovascular risk parameters were measured. Forty-six percent of the patients reported a history of substantial physical or sexual childhood abuse. However, no significant differences in plasma DHEA or DHEA-S emerged in the DST between the traumatised group and the remaining patients. Basal plasma cortisol was significantly lower in the childhood trauma group. No impact of childhood trauma history on cardiovascular risk factor profile was detected. Current limited data about DHEA or DHEA-S in patients with childhood trauma are equivocal. Further study using more sophisticated assessment of trauma history and simultaneously measuring a multitude of putative biomarkers of traumatization are needed.

Glutamatergic Deficits in Schizophrenia - Biomarkers and Pharmacological Interventions within the Ketamine Model.

BACKGROUND: The observation that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists such as ketamine transiently induce schizophrenia-like positive, negative and cognitive symptoms has led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. NMDAR hypofunction can explain many schizophrenia symptoms directly due to excitatory-to-inhibitory (E/I) imbalance, but also dopaminergic dysfunction itself. However, so far no new drug targeting the NMDAR has been successfully approved. In the search for possible biomarkers it is interesting that ketamine-induced psychopathological changes in healthy participants were accompanied by altered electro-(EEG), magnetoencephalographic (MEG) and functional magnetic resonance imaging (fMRI) signals. METHODS: We systematically searched PubMed/Medline and Web of Knowledge databases (January 2006 to July 2017) to identify EEG/MEG and fMRI studies of the ketamine model of schizophrenia with human subjects. The search strategy identified 209 citations of which 46 articles met specified eligibility criteria. RESULTS: In EEG/MEG studies, ketamine induced changes of event-related potentials, such as the P300 potential and the mismatch negativity, similar to alterations observed in schizophrenia patients. In fMRI studies, alterations of activation were observed in different brain regions, most prominently within the anterior cingulate cortex and limbic structures as well as task-relevant brain regions. These alterations were accompanied by changes in functional connectivity, indicating a balance shift of the underlying brain networks. Pharmacological treatments did alter ketamine-induced changes in EEG/MEG and fMRI studies to different extents. CONCLUSION: This review highlights the potential applicability of the ketamine model for schizophrenia drug development by offering the possibility to assess the effect of pharmacological agents on schizophrenia- like symptoms and to find relevant neurophysiological and neuroimaging biomarkers.

Alterations in interhemispheric gamma-band connectivity are related to the emergence of auditory verbal hallucinations in healthy subjects during NMDA-receptor blockade.

Auditory verbal hallucinations (AVH) are a common positive symptom of schizophrenia. Excitatory-to-inhibitory (E/I) imbalance related to disturbed N-methyl-D-aspartate receptor (NMDAR) functioning has been suggested as a possible mechanism underlying altered connectivity and AVH in schizophrenia. The current study examined the effects of ketamine, a NMDAR antagonist, on glutamate-related mechanisms underlying interhemispheric gamma-band connectivity, conscious auditory perception during dichotic listening (DL), and the emergence of auditory verbal distortions and hallucinations (AVD/AVH) in healthy volunteers. In a single-blind, pseudo-randomized, placebo-controlled crossover design, nineteen male, right-handed volunteers were measured using 64 channel electroencephalography (EEG). Psychopathology was assessed with the PANSS interview and the 5D-ASC questionnaire, including a subscale to detect auditory alterations with regard to AVD/AVH (AUA-AVD/AVH). Interhemispheric connectivity analysis was performed using eLORETA source estimation and lagged phase synchronization (LPS) in the gamma-band range (30-100 Hz). Ketamine induced positive symptoms such as hallucinations in a subgroup of healthy subjects. In addition, interhemispheric gamma-band connectivity was found to be altered under ketamine compared to placebo, and subjects with AUA-AVD/AVH under ketamine showed significantly higher interhemispheric gamma-band connectivity than subjects without AUA-AVD/AVH. These findings demonstrate a relationship between NMDAR functioning, interhemispheric connectivity in the gamma-band frequency range between bilateral auditory cortices and the emergence of AVD/AVH in healthy subjects. The result is in accordance with the interhemispheric miscommunication hypothesis of AVH and argues for a possible role of glutamate in AVH in schizophrenia.

Tibial plateau fracture management: arthroscopically-assisted versus ORIF procedure - clinical and radiological comparison.

INTRODUCTION: Tibial plateau fractures are articular injuries that may influence final functional outcome of the knee. Although these fractures comprise only 1% of all fractures, the fracture pattern is usually complex and requires anatomical reduction and absolutely stable fixation to achieve satisfactory results. The development of knee osteoarthritis is a common late complication and it can be strongly influenced by additional, underestimated cartilage defects, and meniscal and ligament tears. MATERIALS AND METHODS: Between January 2012 and February 2015, a total of 78 patients with tibial plateau fractures (Schatzker type I-III) were enrolled in the study. Patients were divided into two groups: one group was treated with arthroscopically-assisted reduction and internal fixation (ARIF) and the other with open reduction and internal fixation (ORIF). The final number of patients was 75; 40 in the ARIF group and 35 in the ORIF group. Radiography and computed tomography were used to assess fracture pattern. An immediate postoperative radiograph was performed, and then repeated at 6 weeks, and 3,6 and 12 months after surgery. Demographic data (age and sex), additional intraarticular injuries, hospital stay and complications were noted, and clinical and radiological Rasmunssen score at 3, 6 and 12 months after surgery were evaluated. RESULTS: Additional intraarticular lesions were found in 27 patients; 20 in the ARIF group and 7 in the ORIF group (p = 0.06). There was a statistically significant difference in average duration of hospital stay: 3.10 ± 0.63 days for the ARIF group and 5.51 ± 1.66 days for the ORIF group (p = 0.0001). All fractures healed within 3 months following surgery. The overall complication rate was 12%. There was no statistically significant difference in complication rate between the two groups (p = 0.63). Clinical and radiological scores were excellent in most patients in both groups. There was no statistically significant difference in average clinical and radiological Rasmunssen scores between the two groups. CONCLUSIONS: Both ARIF and ORIF can provide equally good results; however, ARIF seems to offer a more precise evaluation and treatment of associated intraarticular lesions and to reduce the duration of hospital stay.

Glutamatergic deficit and schizophrenia-like negative symptoms: new evidence from ketamine-induced mismatch negativity alterations in healthy male humans.

BACKGROUND: Targeting the N-methyl-D-aspartate receptor (NMDAR) is a major translational approach for treating negative symptoms of schizophrenia. Ketamine comprehensively produces schizophrenia-like symptoms, such as positive, cognitive and negative symptoms in healthy volunteers. The amplitude of the mismatch negativity (MMN) is known to be significantly reduced not only in patients with schizophrenia, but also in healthy controls receiving ketamine. Accordingly, it was the aim of the present study to investigate whether changes of MMN amplitudes during ketamine administration are associated with the emergence of schizophrenia-like negative symptoms in healthy volunteers. METHODS: We examined the impact of ketamine during an MMN paradigm with 64-channel electroencephalography (EEG) and assessed the psychopathological status using the Positive and Negative Syndrome Scale (PANSS) in healthy male volunteers using a single-blind, randomized, placebo-controlled crossover design. Low-resolution brain electromagnetic tomography was used for source localization. RESULTS: Twenty-four men were included in our analysis. Significant reductions of MMN amplitudes and an increase in all PANSS scores were identified under the ketamine condition. Smaller MMN amplitudes were specifically associated with more pronounced negative symptoms. Source analysis of MMN generators indicated a significantly reduced current source density (CSD) under the ketamine condition in the primary auditory cortex, the posterior cingulate and the middle frontal gyrus. LIMITATIONS: The sample included only men within a tight age range of 20-32 years. CONCLUSION: The MMN might represent a biomarker for negative symptoms in schizophrenia related to an insufficient NMDAR system and could be used to identify patients with schizophrenia with negative symptoms due to NMDAR dysfunction.

Surgical Treatment of Metastatic Disease of the Vertebral Column

Spinal metastatic disease is a rather common occurrence and definitely warrants attention and treatment due to the high likelihood of leaving cancer patients severely disabled in their final months of life. Recent developments in the understanding of the behavior of different tumor types, as well as advances in surgical treatment, are allowing for the evolution of treatment algorithms, especially when surgical treatment is to be considered. This paper gives an overview of the decision-making process and the array of surgical options currently available.

[Hip arthroscopy]. / Artroskopija kuka.

In the last ten years, hip arthroscopy has been developing intensively and it is rapidly gaining primacy in the treatment of various injuries and damages to the hip itself and its immediate vicinity. The basic advantage of hip arthroscopy surgery versus classic open surgery is avoiding an open dislocation of the hip and, thus, reducing patient's morbidity and accelerating his/her rehabilitation, which leads to a quicker return to everyday activities. The success of arthroscopic surgery depends on the correct indication for the surgery and on the experience and the skill of the operator. It also depends on the properly conducted rehabilitation and the patient's compliance, as well as on the patient's realistic expectations. Indications for hip arthroscopy today are the following: injury and damage to acetabular labrum and/or articular cartilage, femoroacetabular impingement syndrome, injuries and damages to the ligament of the femoral head, loose and foreign joint bodies as well as different conditions of synovial membrane (synovial chondromatosis, pigmented villonodular synovitis and other inflammatory arthropathy such as rheumatoid arthritis). In this article we describe the indications, technique, complications and the prospect of hip arthroscopy, with a detailed overview of contemporary literature data.

Current practice variations in the management of anterior cruciate ligament injuries in Croatia.

AIM: To investigate current preferences and opinions on the diagnosis, treatment and rehabilitation of patients with anterior cruciate ligament (ACL) injury in Croatia. METHODS: The survey was conducted using a questionnaire which was sent by e-mail to all 189 members of the Croatian Orthopaedic and Traumatology Association. Only respondents who had performed at least one ACL reconstruction during 2011 were asked to fill out the questionnaire. RESULTS: Thirty nine surgeons responded to the survey. Nearly all participants (95%) used semitendinosus/gracilis tendon autograft for reconstruction and only 5% used bone-patellar tendon-bone autograft. No other graft type had been used. The accessory anteromedial portal was preferred over the transtibial approach (67% vs 33%). Suspensory fixation was the most common graft fixation method (62%) for the femoral side, followed by the cross-pin (33%) and bioabsorbable interference screw (5%). Almost all respondents (97%) used a bioabsorbable interference screw for tibial side graft fixation. CONCLUSION: The results show that ACL reconstruction surgery in Croatia is in step with the recommendations from latest world literature.