Exciting links: imaging and modulation of neural networks underlying key symptoms of schizophrenia

Despite regular treatment, a major part of patients with schizophrenia suffers from auditory verbal hallucinations and/or negative symptoms (reduced energy and motivation, flat affect). To effectively treat these symptoms, it is important to understand the underlying brain mechanisms of these symptoms. Symptoms of schizophrenia are considered a result of disrupted functioning within and between brain networks. The investigation of the brain networks that are involved in the processing of auditory verbal information can give us information about the way patients with auditory verbal hallucinations use these networks in comparison with patients without auditory verbal hallucination. The studies in this thesis show that these networks do not function optimally. Specifically, the network that processes auditory information appears to be too active. In addition, it is known that patients with negative symptoms demonstrate less activation in frontal brain areas, which are closely connected to many other brain regions. In theory, important networks can be stimulated with Transcranial Magnetic Stimulation, such that it can reduce symptomatology. Two placebo controlled clinical trials that applied this technique have been described in this thesis. In the first study, the efficacy of low frequency stimulation of an area that is involved in the processing of auditory verbal information has been investigated. Although on average the active as well as the placebo groups improved, on a symptom level the active treatment did not appear to be more effective than the placebo treatment. However, on a brain level we observed that the active treatment did cause differences. Possibly, optimization of treatment parameters may result in stronger treatment effects. In a second placebo controlled trial, we investigated the effect of high frequency Transcranial Magnetic Stimulation on negative symptoms of schizophrenia. The group that received active treatment improved significantly more on a symptom level than the group that received placebo treatment. In both trials, there were large inter-individual differences in treatment response. Future research should therefore focus on the identification of factors that are related to treatment response, such as demographic variables and brain characteristics (e.g. anatomy and baseline connectivity). The results of this thesis are a good basis for further research on the treatment of auditory verbal hallucinations and negative symptoms in schizophrenia

Improving cognition in severe mental illness by combining cognitive remediation and transcranial direct current stimulation:study protocol for a pragmatic randomized controlled pilot trial (HEADDSET)

Background A fundamental challenge for many people with severe mental illness (SMI) is how to deal with cognitive impairments. Cognitive impairments are common in this population and limit daily functioning. Moreover, neural plasticity in people with SMI appears to be reduced, a factor that might hinder newly learned cognitive skills to sustain. The objective of this pilot trial is to investigate the effects of cognitive remediation (CR) on cognitive and daily functioning in people dependent on residential settings. In addition, transcranial direct current stimulation (tDCS) is used to promote neural plasticity. It is expected that the addition of tDCS can enhance learning and will result in longer-lasting improvements in cognitive and daily functioning. Methods This is a pragmatic, triple-blinded, randomized, sham-controlled, pilot trial following a non-concurrent multiple baseline design with the participants serving as their own control. We will compare (1) CR to treatment as usual, (2) active/sham tDCS+CR to treatment as usual, and (3) active tDCS+CR to sham tDCS+CR. Clinical relevance, feasibility, and acceptability of the use of CR and tDCS will be evaluated. We will recruit 26 service users aged 18 years or older, with a SMI and dependent on residential facilities. After a 16-week waiting period (treatment as usual), which will serve as a within-subject control condition, participants will be randomized to 16 weeks of twice weekly CR combined with active (N = 13) or sham tDCS (N = 13). Cognitive, functional, and clinical outcome assessments will be performed at baseline, after the control (waiting) period, directly after treatment, and 6-months post-treatment. Discussion The addition of cognitive interventions to treatment as usual may lead to long-lasting improvements in the cognitive and daily functioning of service users dependent on residential facilities. This pilot trial will evaluate whether CR on its own or in combination with tDCS can be a clinically relevant addition to further enhance recovery. In case the results indicate that cognitive performance can be improved with CR, and whether or not tDCS will lead to additional improvement, this pilot trial will be extended to a large randomized multicenter study. Trial registration Dutch Trial Registry NL7954. Prospectively registered on August 12, 2019

Glutamate in dorsolateral prefrontal cortex and auditory verbal hallucinations in patients with schizophrenia:A (1)H MRS study

Purpose: Glutamatergic models of psychosis propose that dysfunction of N-methyl-D-aspartate (NMDA) receptors, and associated excess of glutamate, may underlie psychotic experiences in people with schizophrenia. However, little is known about the specific relation between glutamate and auditory verbal hallucinations (AVH) in patients with psychosis. In this study, levels of glutamate + glutamine (Glx) in the left lateral prefrontal lobe were determined using proton magnetic resonance spectroscopy (H-1 MRS) to calculate their association with AVH. Methods: Sixty-seven patients with schizophrenia and thirty healthy control participants (HC) underwent magnetic resonance spectroscopy (MRS) to estimate levels of Glx in the white matter of the left prefrontal lobe. The spectrum was estimated from an 8 mm(3) voxel placed in the left lateral prefrontal region, belonging to both the cingulum and forceps minor. Patients with lifetime AVH (AVH group; n = 45) and patients without lifetime AVH were compared (NoAVH group; n = 22) to control participants. Results: Levels of Glx were significantly different between the groups (F(2,94) = 5.27, p = 0.007). Planned comparisons showed that higher Glx levels were found in control participants than in the total patient group (p = 0.010). However, patients with lifetime AVH had higher levels of Glx compared to patients without lifetime AVH (p = 0.019). Creatin levels were similar in all three groups. We found no association between Gix and the severity of symptoms (item P3 of the PANSS or PANSS positive subscale). Conclusion: The higher Glx levels in patients with lifetime AVH as compared to patients without lifetime AVH suggest a mediating role for Glx in AVH. Our results are consistent with a previous study that found similar decreased levels of Glx in patients with schizophrenia, and increased levels in an AVH group as compared to a NoAVH group. The role of the glutamatergic system deserves further investigation, for example in different brain regions and in relation to clinical variables

Prefrontal NAA and Glx Levels in Different Stages of Psychotic Disorders:a 3T 1H-MRS Study

H-Magnetic Resonance Spectroscopy ((1)H-MRS) can offer insights in various neuropathologies by measuring metabolite levels in the brain. In the current study we investigated the levels of glutamate + glutamine (Glx, neurotransmitter and precursor) and N-Acetyl Aspartate + glutamic acid (NAA + NAAG; neuronal viability) in the prefrontal cortex of patients with a psychotic disorder and people at Ultra High Risk (UHR) for psychosis. A (1)H-MRS spectrum was acquired in 31 patients with a recent onset psychotic disorder and 60 with a chronic state, 16 UHR patients and 36 healthy controls. Absolute metabolite levels were calculated using LCModel with a reference water peak. Groups were compared while taking into account age and partial volume effects. Moreover, we investigated associations with positive and negative symptoms, duration of illness, and antipsychotic treatment in patients. The most notable finding is that chronicity of schizophrenia was related to decreased levels of Glx and NAA. On the other hand, although on an exploratory note, UHR showed increased levels of prefrontal Glx and NAA levels with increasing age. Our results may indicate an initial Glx and NAA increase and subsequent decrease during illness progression that may be related to the neurotoxic effects of glutamate

Hyperemesis gravidarum severity, enteral tube feeding and cardiometabolic markers in offspring cord blood

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Thyroid-stimulating hormone and free thyroxine fail to predict the severity and clinical course of hyperemesis gravidarum : A prospective cohort study

Funding information: This prospective cohort study was supported by a research grant from North West Hospital Group, Alkmaar, the Netherlands (Grant number: 2013T085) and by a research grant from the Amsterdam Reproduction and Development (AR&D) Research Institute, Amsterdam UMC, the Netherlands (Project number: 23346). ACKNOWLEDGMENTS We thank Dr. J.P. Bestwick (employed at Queen Mary University of London, London, UK) and Professor Dr. J.H. Lazarus (employed at Cardiff School of Medicine, Cardiff, UK) for providing TSH medians from their study in the UK. Dr. J.P. Bestwick and Professor Dr. Lazarus have nothing to disclose.Peer reviewedPublisher PD