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BackgroundAberrant anticipation of motivational salient events and processing of outcome evaluation in striatal and prefrontal regions have been suggested to underlie psychosis. Altered glutamate levels have likewise been linked to schizophrenia. Glutamatergic abnormalities may affect the processing of motivational salience and outcome evaluation. It remains unresolved, whether glutamatergic dysfunction is associated with the coding of motivational salience and outcome evaluation in antipsychotic-naïve patients with first-episode psychosis.MethodsFifty-one antipsychotic-naïve patients with first-episode psychosis (22 ± 5.2 years, female/male: 31/20) and 52 healthy controls (HC) matched on age, sex, and parental education underwent functional magnetic resonance imaging and magnetic resonance spectroscopy (3T) in one session. Brain responses to motivational salience and negative outcome evaluation (NOE) were examined using a monetary incentive delay task. Glutamate levels were estimated in the left thalamus and anterior cingulate cortex using LCModel.ResultsPatients displayed a positive signal change to NOE in the caudate (p = 0.001) and dorsolateral prefrontal cortex (DLPFC; p = 0.003) compared to HC. No group difference was observed in motivational salience or in levels of glutamate. There was a different association between NOE signal in the caudate and DLPFC and thalamic glutamate levels in patients and HC due to a negative correlation in patients (caudate: p = 0.004, DLPFC: p = 0.005) that was not seen in HC.ConclusionsOur findings confirm prior findings of abnormal outcome evaluation as a part of the pathophysiology of schizophrenia. The results also suggest a possible link between thalamic glutamate and NOE signaling in patients with first-episode psychosis.

Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined.

BackgroundThe typical onset of schizophrenia coincides with the maturational peak in cognition; however, for a significant proportion of patients the onset is before age 18 and after age 30 years. While cognitive deficits are considered core features of schizophrenia, few studies have directly examined the impact of age of illness onset on cognition.MethodsThe aim of the study was to examine if the effects of age on cognition differ between healthy controls (HCs) and patients with schizophrenia at illness onset. We examined 156 first-episode antipsychotic-naïve patients across a wide age span (12–43 years), and 161 age- and sex-matched HCs. Diagnoses were made according to ICD-10 criteria. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS), and IQ was estimated using subtests from the Wechsler adult- or child-intelligence scales. Multivariate analysis of covariance (MANCOVA) was used to examine linear and quadratic effects of age on cognitive scores and interactions by group, including sex and parental socioeconomic status as covariates.ResultsThere was a significant overall effect of age on BACS and IQ (p < 0.001). Significant group-by-age interactions for verbal memory (for age-squared, p = 0.009), and digit sequencing (for age, p = 0.01; age-squared, p < 0.001), indicated differential age-related trajectories between patients and HCs.ConclusionsCognitive functions showing protracted maturation into adulthood, such as verbal memory and verbal working memory, may be particularly impaired in both early- and late-schizophrenia onset. Our findings indicate a potential interaction between the timing of neurodevelopmental maturation and a possible premature age effect in late-onset schizophrenia.

Disturbances in the brain glutamate and GABA (γ-aminobutyric acid) homeostasis may be markers of transition to psychosis in individuals at high-risk (HR). Knowledge of GABA and glutamate levels in HR stages could give an insight into changes in the neurochemistry underlying psychosis. Studies on glutamate in HR have provided conflicting data, and GABA studies have only recently been initialized. In this meta-analysis, we compared cerebral levels of glutamate and GABA in HR individuals with healthy controls (HC). We searched Medline and Embase for articles published on 1H-MRS studies on glutamate and GABA in HR states until April 9th, 2019. We identified a total of 28 eligible studies, of which eight reported GABA (243 HR, 356 HC) and 26 reported glutamate (299 HR, 279 HC) or Glx (glutamate + glutamine) (584 HR, 632 HC) levels. Sample sizes varied from 6 to 75 for HR and 10 to 184 for HC. Our meta-analysis of 1H-MRS studies on glutamate and GABA in HR states displayed significantly lower (P = 0.0003) levels of thalamic glutamate in HR individuals than in HC and significantly higher (P = 0.001) Glx in the frontal lobe of genetic HR individuals (1st-degree relatives) than in HC. No other significant differences in glutamate and GABA levels were found. Subject numbers in the studies on glutamate as well as GABA levels were generally small and the data conflicting. Our meta-analytical findings highlight the need for larger and more homogeneous studies of glutamate and GABA in high-risk states.

Background: Dopamine activity has been associated with the response to antipsychotic treatment. Our study used a four-parameter model to test the association between the striatal decarboxylation rate of 18F-DOPA to 18F-dopamine (k3) and the effect of treatment on psychotic symptoms in antipsychotic-naïve patients with first-episode psychosis. We further explored the effect of treatment with a partial dopamine D2 receptor agonist (aripiprazole) on k3 and dopamine synthesis capacity (DSC) determined by the four-parameter model and by the conventional tissue reference method. Methods: Sixty-two individuals (31 patients and 31 control subjects) underwent 18F-DOPA positron emission tomography at baseline, and 15 patients were re-examined after 6 weeks. Clinical re-examinations were completed after 6 weeks (n = 28) and 6 months (n = 15). Symptoms were evaluated with the Positive and Negative Syndrome Scale. Results: High baseline decarboxylation rates (k3) were associated with more positive symptoms at baseline (p < .001) and with symptom improvement after 6 weeks (p = .006). Subregion analyses showed that baseline k3 for the putamen (p = .003) and nucleus accumbens (p = .013) and DSC values for the nucleus accumbens (p = .003) were associated with psychotic symptoms. The tissue reference method yielded no associations between DSC and symptoms or symptom improvement. Neither method revealed any effects of group or treatment on average magnitudes of k3 or DSC, whereas changes in dopamine synthesis were correlated with higher baseline values, implying a potential effect of treatment. Conclusions: Striatal decarboxylation rate at baseline was associated with psychotic symptoms and treatment response. The strong association between k3 and treatment effect potentially implicate on new treatment strategies.

Arterial spin labelling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that may provide fully quantitative regional cerebral blood flow (rCBF) images. However, before its application in clinical routine, ASL needs to be validated against the clinical gold standard, 15O-H2O positron emission tomography (PET). We aimed to compare the two techniques by performing simultaneous quantitative ASL-MRI and 15O-H2O-PET examinations in a hybrid PET/MRI scanner. Duplicate rCBF measurements were performed in healthy young subjects ( n = 14) in rest, during hyperventilation, and after acetazolamide (post-ACZ), yielding 63 combined PET/MRI datasets in total. Average global CBF by ASL-MRI and 15O-H2O-PET was not significantly different in any state (40.0 ± 6.5 and 40.6 ± 4.1 mL/100 g/min, respectively in rest, 24.5 ± 5.1 and 23.4 ± 4.8 mL/100 g/min, respectively, during hyperventilation, and 59.1 ± 10.4 and 64.7 ± 10.0 mL/100 g/min, respectively, post-ACZ). Overall, strong correlation between the two methods was found across all states (slope = 1.01, R2 = 0.82), while the correlations within individual states and of reactivity measures were weaker, in particular in rest (R2 = 0.05, p = 0.03). Regional distribution was similar, although ASL yielded higher perfusion and absolute reactivity in highly vascularized areas. In conclusion, ASL-MRI and 15O-H2O-PET measurements of rCBF are highly correlated across different perfusion states, but with variable correlation within and between hemodynamic states, and systematic differences in regional distribution.

Objective Several studies have found an increase in hippocampal volume following electroconvulsive therapy (ECT), but the effect on cortical thickness has been less investigated. We aimed to examine the effects of ECT on cortical thickness and their associations with clinical outcome. Method Using 3 Tesla MRI scanner, we obtained T1-weighted brain images of 18 severely depressed patients at three time points: before, right after and 6 months after a series of ECT. The thickness of 68 cortical regions was extracted using Free Surfer, and Linear Mixed Model was used to analyze the longitudinal changes. Results We found significant increases in cortical thickness of 26 regions right after a series of ECT, mainly within the frontal, temporal and insular cortex. The thickness returned to the baseline values at 6-month follow-up. We detected no significant decreases in cortical thickness. The increase in the thickness of the right lateral orbitofrontal cortex was associated with a greater antidepressant effect, r = 0.75, P = 0.0005. None of the cortical regions showed any associations with cognitive side effects. Conclusion The increases in cortical thickness induced by ECT are transient. Further multimodal MRI studies should examine the neural correlates of these increases and their relationship with the antidepressant effect.

Spreading depolarizations (SDs) occur in 50–60% of patients after surgical treatment of severe traumatic brain injury (TBI) and are independently associated with unfavorable outcomes. Here we performed a pilot study to examine the relationship between SDs and various types of intracranial lesions, progression of parenchymal damage, and outcomes. In a multicenter study, fifty patients (76% male; median age 40) were monitored for SD by continuous electrocorticography (ECoG; median duration 79 h) following surgical treatment of severe TBI. Volumes of hemorrhage and parenchymal damage were estimated using unbiased stereologic assessment of preoperative, postoperative, and post-ECoG serial computed tomography (CT) studies. Neurologic outcomes were assessed at 6 months by the Glasgow Outcome Scale-Extended. Preoperative volumes of subdural and subarachnoid hemorrhage, but not parenchymal damage, were significantly associated with the occurrence of SDs (P’s

Whether aberrant cerebral blood flow (CBF) in schizophrenia is affected by genetic influences, and consequently a potential marker for genetic susceptibility, is unknown. Our aims were to determine the heritability of CBF in thalamic, frontal, and striatal areas, and to ascertain if associations with disease were under genetic influence. Monozygotic (MZ) twin pairs concordant (n = 2) or discordant (n = 20) for schizophrenia spectrum disorders (ICD-10 F2x.x), matched on sex and age with dizygotic (DZ; n = 20) and healthy control pairs (MZ: n = 27; DZ: n = 18; total: n = 181 individuals), were recruited via the National Danish Twin Register. CBF in thalamus, frontal lobes, and putamen was measured with pseudo-continuous arterial spin labeling on a 3 T magnetic resonance scanner. Twin statistics were performed with structural equation modeling. CBF in the frontal lobes was heritable (h2 = 0.44, 95% CI [0.22–0.60]) but not correlated to disease. CBF correlated to schizophrenia spectrum disorders in the left thalamus (r = 0.17, [0.03–0.31]; P = 0.02), as well as in the left putamen (r = 0.19, [0.05–0.32]; P = 0.007) and the right putamen (r = 0.18, [0.03–0.32]; P = 0.02). When restricting the sample to schizophrenia (F20.x) only, shared genetic influences between CBF in the left putamen and schizophrenia liability (phenotypic correlation = 0.44, [0.28–0.58], P < 0.001) were found. Our results provide heritability estimates of CBF in the frontal lobes, and we find CBF in thalamus and putamen to be altered in schizophrenia spectrum disorders. Furthermore, shared genetic factors influence schizophrenia liability and striatal perfusion. Specifically, higher perfusion in the left putamen may constitute a marker of genetic susceptibility for schizophrenia.

BackgroundPsychotic symptoms have been linked to salience abnormalities in the brain reward system, perhaps caused by a dysfunction of the dopamine neurotransmission in striatal regions. Blocking dopamine D2 receptors dampens psychotic symptoms and normalises reward disturbances, but a direct relationship between D2 receptor blockade, normalisation of reward processing and symptom improvement has not yet been demonstrated. The current study examined the association between blockade of D2 receptors in the caudate nucleus, alterations in reward processing and the psychopathology in a longitudinal study of antipsychotic-naïve first-episode schizophrenia patients.MethodsTwenty-two antipsychotic-naïve first-episode schizophrenia patients (10 males, mean age 23.3) and 23 healthy controls (12 males, mean age 23.5) were examined with single-photon emission computed tomography using 123I-labelled iodobenzamide. Reward disturbances were measured with functional magnetic resonance imaging (fMRI) using a modified version of the monetary-incentive-delay task. Patients were assessed before and after 6 weeks of treatment with amisulpride.ResultsIn line with previous results, patients had a lower fMRI response at baseline (0.2 ± 0.5 v. 0.7 ± 0.6; p = 0.008), but not at follow-up (0.5 ± 0.6 v. 0.6 ± 0.7), and a change in the fMRI signal correlated with improvement in Positive and Negative Syndrome Scale positive symptoms (ρ = −0.435, p = 0.049). In patients responding to treatment, a correlation between improvement in the fMRI signal and receptor occupancy was found (ρ = 0.588; p = 0.035).ConclusionThe results indicate that salience abnormalities play a role in the reward system in schizophrenia. In patients responding to a treatment-induced blockade of dopamine D2 receptors, the psychotic symptoms may be ameliorated by normalising salience abnormalities in the reward system.

Quantitative measurements of resting cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) show large between-subject and regional variability, but the relationships between CBF and CMRO2 measurements regionally and globally are not fully established. Here, we investigated the between-subject and regional associations between CBF and CMRO2 measures with independent and quantitative PET techniques. We included resting CBF and CMRO2 measurements from 50 healthy volunteers (aged 22–81yr), and calculated the regional and global values of oxygen delivery (DO2) and oxygen extraction fraction (OEF). Linear mixed-model analysis showed that CBF and CMRO2 measurements were closely associated regionally, but no significant between-subject association could be demonstrated, even when adjusting for arterial PCO2 and hemoglobin concentration. The analysis also showed regional differences of OEF, reflecting variable relationship between DO2 and CMRO2, resulting in lower estimates of OEF in thalami, brainstem, and mesial temporal cortices and higher estimates of OEF in occipital cortex. In the present study, we demonstrated no between-subject association of quantitative measurements of CBF and CMRO2 in healthy subjects. Thus, quantitative measurements of CBF did not reflect the underlying between-subject variability of oxygen metabolism measures, mainly because of large interindividual OEF variability not accounted for by PCO2 and hemoglobin concentration. NEW & NOTEWORTHY Using quantitative PET-measurements in healthy human subjects, we confirmed a regional association of CBF and CMRO2, but did not find an association of these values across subjects. This suggests that subjects have an individual coupling between perfusion and metabolism and shows that absolute perfusion measurements does not serve as a surrogate measure of individual measures of oxygen metabolism. The analysis further showed smaller, but significant regional differences of oxygen extraction fraction at rest.

Cerebral white matter (WM) aberrations in schizophrenia have been linked to multiple neurobiological substrates but the underlying mechanisms remain unknown. Moreover, antipsychotic treatment and substance use constitute potential confounders. Multimodal studies using diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) may provide deeper insight into the whole brain WM pathophysiology in schizophrenia. We combined DTI and MTI to investigate WM integrity in 51 antipsychotic-naïve, first-episode schizophrenia patients and 55 matched healthy controls, using 3 T magnetic resonance imaging (MRI). Psychopathology was assessed with the positive and negative syndrome scale (PANSS). A whole brain partial least squares correlation (PLSC) method was used to conjointly analyze DTI-derived measures (fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), mode of anisotropy (MO)) and the magnetization transfer ratio (MTR) to identify group differences, and associations with psychopathology. In secondary analyses, we excluded recreational substance users from both groups resulting in 34 patients and 51 healthy controls. The primary PLSC group difference analysis identified a significant pattern of lower FA, AD, MO and higher RD in patients (p = 0.04). This pattern suggests disorganized WM microstructure in patients. The secondary PLSC group difference analysis without recreational substance users revealed a significant pattern of lower FA and higher AD, RD, MO, MTR in patients (p = 0.04). This pattern in the substance free patients is consistent with higher extracellular free-water concentrations, which may reflect neuroinflammation. No significant associations with psychopathology were observed. Recreational substance use appears to be a confounding issue, which calls for attention in future WM studies.

Background Abnormal glutamate and GABA (gamma-aminobutyric acid) levels have been found in the early phase of schizophrenia and may underlie cognitive deficits. However, the association between cognitive function and levels of glutamatergic metabolites and GABA has not been investigated in a large group of antipsychotic-naive patients. Methods In total, 56 antipsychotic-naive patients with schizophrenia or psychotic disorder and 51 healthy control subjects underwent magnetic resonance spectroscopy to measure glutamate, glutamate+glutamine (Glx), and GABA levels in dorsal anterior cingulate cortex (ACC) and glutamate and Glx levels in left thalamus. The cognitive domains of attention, working memory, and IQ were assessed. Results The whole group of antipsychotic-naive patients had lower levels of GABA in dorsal ACC (p = .03), and the subgroup of patients with a schizophrenia diagnosis had higher glutamate levels in thalamus (p = .01), but Glx levels in dorsal ACC and thalamus did not differ between groups. Glx levels in dorsal ACC were positively associated with working memory (logarithmically transformed: b = −.016 [higher score indicates worse performance], p = .005) and attention (b = .056, p = .035) in both patients and healthy control subjects, although the association with attention did not survive adjustment for multiple comparisons. Conclusions The findings suggest a positive association between glutamatergic metabolites and cognitive function that do not differ between patients and healthy control subjects. Moreover, our data indicate that decreased GABAergic levels in dorsal ACC are involved in schizophrenia and psychotic disorder, whereas increased glutamate levels in thalamus seem to be implicated in schizophrenia pathophysiology. The findings imply that first-episode patients with cognitive deficits may gain from glutamate-modulating compounds.

Background Cognitive functions have been associated with white matter (WM) microstructure in schizophrenia, but most studies are limited by examining only select cognitive measures and single WM tracts in chronic, medicated patients. It is unclear if the cognition-WM relationship differs between antipsychotic-naive patients with schizophrenia and healthy controls, as differential associations have not been directly examined. Here we examine if there are differential patterns of associations between cognition and WM microstructure in first-episode antipsychotic-naive patients with schizophrenia and healthy controls, and we characterize reliable contributors to the pattern of associations across multiple cognitive domains and WM regions, in order to elucidate white matter contribution to the neural underpinnings of cognitive deficits. Methods Thirty-six first-episode antipsychotic-naive patients with schizophrenia and 52 matched healthy controls underwent cognitive tests and diffusion-weighted imaging on a 3T Magnetic Resonance Imaging scanner. Using a multivariate partial least squares correlation analysis, we included 14 cognitive variables and mean fractional anisotropy values of 48 WM regions. Results Initial analyses showed significant group differences in both measures of WM and cognition. There was no group interaction effect in the pattern of associations between cognition and WM microstructure. The combined analysis of patients and controls lead to a significant pattern of associations (omnibus test p = .015). Thirty-four regions and seven cognitive functions contributed reliably to the associations. Conclusions The lack of an interaction effect suggests similar associations in first-episode antipsychotic-naive patients with schizophrenia and healthy controls. This, together with the differences in both WM and cognitive measurements, supports the involvement of WM in cognitive deficits in schizophrenia. Our findings add to the field by showing a coherent picture of the overall pattern of association between cognition and WM. These findings increase our understanding of the impact of WM on cognition, contributing to the search for neuromarkers of cognitive deficits in schizophrenia.

Background: Psychological traumatic experiences can lead to posttraumatic stress disorder (PTSD). Secondary psychotic symptoms are not common but may occur. Objectives: Since psychotic symptoms of schizophrenia have been related to aberrant reward processing in the striatum, using the same paradigm we investigate whether the same finding extends to psychotic and anhedonic symptoms in PTSD. Methods: A total of 70 male refugees: 18 PTSD patients with no secondary psychotic symptoms (PTSD-NSP), 21 PTSD patients with secondary psychotic symptoms (PTSD-SP), and 31 healthy controls (RHC) were interviewed and scanned with functional magnetic resonance imaging (fMRI) during a monetary incentive delay task. Using region of interest analysis of the prefrontal cortex and ventral striatum, we investigated reward-related activity. Results: Compared to RHC, participants with PTSD had decreased neural activity during monetary reward. Also, participants with PTSD-SP exhibited decreased activity in the associative striatum relative to participants with PTSD-NSP during processing of motivational reward anticipation which correlated with severity of psychotic symptoms. However, the difference between the two PTSD groups disappeared when PTSD severity and trauma exposure were accounted for. Conclusions: Anhedonia and secondary psychotic symptoms in PTSD are characterized by dysfunctional reward consumption and anticipation processing, respectively. The latter may reflect a mechanism by which abnormal reward signals in the basal ganglia facilitates psychotic symptoms across psychiatric conditions.

The reproducibility of machine-learning analyses in computational psychiatry is a growing concern. In a multimodal neuropsychiatric dataset of antipsychotic-naïve, first-episode schizophrenia patients, we discuss a workflow aimed at reducing bias and overfitting by invoking simulated data in the design process and analysis in two independent machine-learning approaches, one based on a single algorithm and the other incorporating an ensemble of algorithms. We aimed to (1) classify patients from controls to establish the framework, (2) predict short- and long-term treatment response, and (3) validate the methodological framework. We included 138 antipsychotic-naïve, first-episode schizophrenia patients with data on psychopathology, cognition, electrophysiology, and structural magnetic resonance imaging (MRI). Perinatal data and long-term outcome measures were obtained from Danish registers. Short-term treatment response was defined as change in Positive And Negative Syndrome Score (PANSS) after the initial antipsychotic treatment period. Baseline diagnostic classification algorithms also included data from 151 matched controls. Both approaches significantly classified patients from healthy controls with a balanced accuracy of 63.8% and 64.2%, respectively. Post-hoc analyses showed that the classification primarily was driven by the cognitive data. Neither approach predicted short- nor long-term treatment response. Validation of the framework showed that choice of algorithm and parameter settings in the real data was successfully guided by results from the simulated data. In conclusion, this novel approach holds promise as an important step to minimize bias and obtain reliable results with modest sample sizes when independent replication samples are not available.

It is thought that the hippocampal neurogenesis is an important mediator of the antidepressant effect of electroconvulsive therapy (ECT). However, most previous studies failed to demonstrate the relationship between the increase in the hippocampal volume and the antidepressant effect. We reinvestigated this relationship by looking at distinct hippocampal subregions and applying repeated measures correlation. Using a 3 Tesla MRI-scanner, we scanned 22 severely depressed in-patients at three time points: before the ECT series, after the series, and at six-month follow-up. The depression severity was assessed by the 17-item Hamilton Rating Scale for Depression (HAMD-17). The hippocampus was segmented into subregions using Freesurfer software. The dentate gyrus (DG) was the primary region of interest (ROI), due to the role of this region in neurogenesis. The other major hippocampal subregions were the secondary ROIs (n = 20). The general linear mixed model and the repeated measures correlation were used for statistical analyses. Immediately after the ECT series, a significant volume increase was present in the right DG (Cohen's d = 1.7) and the left DG (Cohen's d = 1.5), as well as 15 out of 20 secondary ROIs. The clinical improvement, i.e., the decrease in HAMD-17 score, was correlated to the increase in the right DG volume (rrm = −0.77, df = 20, p

Patients with chronic schizophrenia often display enlarged striatal volumes, and antipsychotic drugs may contribute via the dopamine D2/3 receptor (D2/3R) blockade. Separating the effects of disease from medication is challenging due to the lack of a proper placebo-group. To address this, we conducted a longitudinal study of antipsychotic-naïve, first-episode schizophrenia patients to test the hypothesis that selective blockade of D2/3R would induce a dose-dependent striatal volume increase. Twenty-one patients underwent structural magnetic resonance imaging (sMRI), single-photon emission computed tomography (SPECT), and symptom severity ratings before and after six weeks of amisulpride treatment. Twenty-three matched healthy controls underwent sMRI and baseline SPECT. Data were analyzed using repeated measures and multiple regression analyses. Correlations between symptom severity decrease, volume changes, dose and receptor occupancy were explored. Striatal volumes did not differ between patients and controls at baseline or follow-up, but a significant group-by-time interaction was found (p = 0.01). This interaction was explained by a significant striatal volume increase of 2.1% in patients (Cohens d = 0.45). Striatal increase was predicted by amisulpride dose, but not by either D2/3R occupancy or baseline symptom severity. A significant reduction in symptom severity was observed at a mean dose of 233.3 (SD = 109.9) mg, corresponding to D2/3R occupancy of 44.65%. Reduction in positive symptoms correlated significantly with striatal volume increase, driven by reductions in hallucinations. Our data demonstrate a clear link between antipsychotic treatment and striatal volume increase in antipsychotic-naïve schizophrenia patients. Moreover, the treatment-induced striatal volume increase appears clinically relevant by correlating to reductions in core symptoms of schizophrenia.

BackgroundSymptoms of anhedonia are often central to posttraumatic stress disorder (PTSD), but it is unclear how anhedonia is affected by processes induced by reliving past traumatic memories.MethodsSixty-nine male refugees (PTSD = 38) were interviewed and scanned with functional magnetic resonance imaging while viewing positive, neutral and Scrambled Pictures after being read personalized scripts evoking an emotionally neutral memory and a traumatic memory. We further measured postprovocation state symptoms, physiological measures and PTSD symptoms. We tested whether neural activity associated with positive picture viewing in participants with PTSD was differentially affected by symptom provocation compared to controls.ResultsFor the pictures > scrambled contrast (Positive contrast), PTSD participants had significantly less activity than controls in fusiform gyrus, right inferior temporal gyrus and left middle occipital gyrus. The Positive contrast activity in fusiform gyrus scaled negatively with anhedonia symptoms in PTSD participants after controlling for total PTSD severity. Relative to the emotionally Neutral Script, the Trauma Script decreased positive picture viewing activity in posterior cingulate cortex, precuneus and left calcarine gyrus, but there was no difference between PTSD participants and controls.ConclusionsWe found reduced responsiveness of higher visual processing of emotionally positive pictures in PTSD. The significant correlation found between positive picture viewing activity and anhedonia suggests the reduced responsiveness to be due to the severity of anhedonia.

New treatments for cerebral small-vessel disease are needed to reduce the risk of small-vessel occlusion stroke and vascular cognitive impairment. We investigated an approach targeted to the signalling molecule cyclic guanosine monophosphate, using the phosphodiesterase 5 inhibitor tadalafil, to explore if it improves cerebral blood flow and endothelial function in patients with cerebral small-vessel disease and stroke. In a randomized, double-blinded, placebo-controlled, cross-over pilot trial (NCT02801032), we included patients who had a previous (>6 months) small-vessel occlusion stroke. They received a single dose of either 20 mg tadalafil or placebo on 2 separate days at least 1 week apart. We measured the following: baseline MRI for lesion load, repeated measurements of blood flow velocity in the middle cerebral artery by transcranial Doppler, blood oxygen saturation in the cortical microvasculature by near-infrared spectroscopy, peripheral endothelial response by EndoPAT and endothelial-specific blood biomarkers. Twenty patients with cerebral small-vessel disease stroke (3 women, 17 men), mean age 67.1 ± 9.6, were included. The baseline mean values ± standard deviations were as follows: blood flow velocity in the middle cerebral artery, 57.4 ± 10.8 cm/s; blood oxygen saturation in the cortical microvasculature, 67.0 ± 8.2%; systolic blood pressure, 145.8 ± 19.5 mmHg; and diastolic blood pressure, 81.3 ± 9.1 mmHg. We found that tadalafil significantly increased blood oxygen saturation in the cortical microvasculature at 180 min post-administration with a mean difference of 1.57 ± 3.02%. However, we saw no significant differences in transcranial Doppler measurements over time. Tadalafil had no effects on peripheral endothelial function assessed by EndoPAT and endothelial biomarker results conflicted. Our findings suggest that tadalafil may improve vascular parameters in patients with cerebral small-vessel disease stroke, although the effect size was small. Increased oxygenation of cerebral microvasculature during tadalafil treatment indicated improved perfusion in the cerebral microvasculature, theoretically presenting an attractive new therapeutic target in cerebral small-vessel disease. Future studies of the effect of long-term tadalafil treatment on cerebrovascular reactivity and endothelial function are needed to evaluate general microvascular changes and effects in cerebral small-vessel disease and stroke., A reduced cerebral blood flow is well known in cerebral small-vessel disease. In this pilot trial, we found that tadalafil may increase cerebral microperfusion in small-vessel occlusion stroke. This is interesting, since it suggests a new target in treating this cerebrovascular disease. A larger clinical trial is planned., Graphical Abstract

Studies exploring age-related brain and cognitive change have identified substantial heterogeneity among individuals, but the underlying reasons for the differential trajectories remain largely unknown. We investigated cross-sectional and longitudinal associations between brain-imaging phenotypes (IDPs) and cognitive ability, and how these relations may be modified by common risk and protective factors. Participants were recruited from the 1953 Danish Male Birth Cohort (N=123), a longitudinal study of cognitive and brain ageing. Childhood IQ and socio-demographic factors are available for these participants who have been assessed regularly on multiple IDPs and behavioural factors in midlife. Using Pearson correlations and canonical correlation analysis (CCA), we explored the relation between 454 IDPs and 114 behavioural variables. CCA identified a single mode of population covariation coupling cross-subject longitudinal changes in brain structure to changes in cognitive performance and to a range of age-related covariates (r=0.92, Pcorrected < 0.001). Specifically, this CCA-mode indicated that; decreases in IQ and speed assessed tasks, higher rates of familial myocardial infarct, less physical activity, and poorer mental health are associated with larger decreases in whole brain grey matter and white matter. We found no evidence supporting the role of baseline scores as predictors of impending brain and behavioural change in late-midlife.

BackgroundPoor response to dopaminergic antipsychotics constitutes a major challenge in the treatment of psychotic disorders and markers for non-response during first-episode are warranted. Previous studies have found increased levels of glutamate and γ-aminobutyric acid (GABA) in non-responding first-episode patients compared to responders, but it is unknown if non-responders can be identified using reference levels from healthy controls (HCs).MethodsThirty-nine antipsychotic-naïve patients with first-episode psychosis and 36 matched HCs underwent repeated assessments with the Positive and Negative Syndrome Scale and 3T magnetic resonance spectroscopy. Glutamate scaled to total creatine (/Cr) was measured in the anterior cingulate cortex (ACC) and left thalamus, and levels of GABA/Cr were measured in ACC. After 6 weeks, we re-examined 32 patients on aripiprazole monotherapy and 35 HCs, and after 26 weeks we re-examined 30 patients on naturalistic antipsychotic treatment and 32 HCs. The Andreasen criteria defined non-response.ResultsBefore treatment, thalamic glutamate/Cr was higher in the whole group of patients but levels normalized after treatment. ACC levels of glutamate/Cr and GABA/Cr were lower at all assessments and unaffected by treatment. When compared with HCs, non-responders at week 6 (19 patients) and week 26 (16 patients) had higher baseline glutamate/Cr in the thalamus. Moreover, non-responders at 26 weeks had lower baseline GABA/Cr in ACC. Baseline levels in responders and HCs did not differ.ConclusionGlutamatergic and GABAergic abnormalities in antipsychotic-naïve patients appear driven by non-responders to antipsychotic treatment. If replicated, normative reference levels for glutamate and GABA may aid estimation of clinical prognosis in first-episode psychosis patients.

Background. Cerebral glutamate and gamma-aminobutyric acid (GABA) levels might predict clinical outcome in individuals at ultrahigh risk (UHR) for psychosis but have previously primarily been investigated in smaller cohorts. We aimed to study whether baseline levels of glutamate and GABA in anterior cingulate cortex (ACC) and glutamate in thalamus could predict remission status and whether baseline metabolites differed in the remission versus the nonremission group. We also investigated the relationship between baseline metabolite levels and severity of clinical symptoms, functional outcome, and cognitive deficits at follow-up. Methods. About 124 UHR individuals were recruited at baseline. In this, 74 UHR individuals were clinically and cognitively assessed after 12 months, while remission status was available for 81 (25 remission/56 nonremission). Glutamate and GABA levels were assessed at baseline using 3 T proton magnetic resonance spectroscopy. Psychopathology, symptom severity, and remission were assessed with the Comprehensive Assessment of At-Risk Mental States and Clinical Global Impression and functional outcome with the Social and Occupational Functioning Assessment Scale. Cognitive function was estimated with the Cambridge Neuropsychological Test Automated Battery. Results. There were no differences between baseline glutamate and GABA levels in subjects in the nonremission group compared with the remission group, and baseline metabolites could not predict remission status. However, higher baseline levels of GABA in ACC were associated with clinical global improvement (r = −0.34, N = 51, p = 0.01) in an explorative analysis. Conclusions. The variety in findings across studies suggests a probable multifactorial influence on clinical outcome in UHR individuals. Future studies should combine multimodal approaches to attempt prediction of long-term outcome.

BackgroundA wealth of clinical studies have identified objective biomarkers, which separate schizophrenia patients from healthy controls on a group level, but current diagnostic systems solely include clinical symptoms. In this study, we investigate if machine learning algorithms on multimodal data can serve as a framework for clinical translation.MethodsForty-six antipsychotic-naïve, first-episode schizophrenia patients and 58 controls underwent neurocognitive tests, electrophysiology, and magnetic resonance imaging (MRI). Patients underwent clinical assessments before and after 6 weeks of antipsychotic monotherapy with amisulpride. Nine configurations of different supervised machine learning algorithms were applied to first estimate the unimodal diagnostic accuracy, and next to estimate the multimodal diagnostic accuracy. Finally, we explored the predictability of symptom remission.ResultsCognitive data significantly classified patients from controls (accuracies = 60–69%;pvalues = 0.0001–0.009). Accuracies of electrophysiology, structural MRI, and diffusion tensor imaging did not exceed chance level. Multimodal analyses with cognition plus any combination of one or more of the remaining three modalities did not outperform cognition alone. None of the modalities predicted symptom remission.ConclusionsIn this multivariate and multimodal study in antipsychotic-naïve patients, only cognition significantly discriminated patients from controls, and no modality appeared to predict short-term symptom remission. Overall, these findings add to the increasing call for cognition to be included in the definition of schizophrenia. To bring about the full potential of machine learning algorithms in first-episode, antipsychotic-naïve schizophrenia patients, carefula priorivariable selection based on independent data as well as inclusion of other modalities may be required.

Whether migraine headache and migraine aura share common pathophysiological mechanisms remains to be understood. Cilostazol causes cAMP accumulation and provokes migraine-like headache in migraine patients without aura. We investigated if cilostazol induces aura and migraine-like headache in patients with migraine with aura and alters peripheral endothelial function and levels of endothelial markers. In a randomized, double-blinded, placebo-controlled crossover study, 16 patients with migraine with aura (of whom 12 patients exclusively had attacks of migraine with aura) received 200 mg cilostazol (Pletal ®) or placebo on two separate days. The development, duration, and characteristics of aura and headache were recorded using a questionnaire. Peripheral endothelial function was assessed by digital pulse amplitude tonometry using EndoPAT2000, and endothelial markers (VCAM1, E-selectin, and VEGFA) were measured. After administration of cilostazol, 14 patients (88%) experienced headache compared with six patients (38%) after placebo (P = 0.009). The headache in 12 patients (75%) after cilostazol and one patient (6%) after placebo fulfilled the criteria for migraine-like attacks (P = 0.0002). Patients reported that the attack mimicked the headache phase during their usual migraine attacks. However, aura symptoms were elicited in one patient after cilostazol and one patient after placebo. Further, endothelial function, as assessed by peripheral arterial tonometry, and endothelial markers were not significantly altered by cilostazol. Accumulation of cAMP by cilostazol induces migraine-like headache, but not aura, in patients with migraine with aura, even in those who exclusively reported attacks of migraine with aura in their spontaneous attacks. These findings further support dissociation between the aura and the headache phase with a yet unknown trigger for the aura and link between aura and headache. In addition, cilostazol administration did not significantly alter endothelial function, as assessed by peripheral arterial tonometry, or the endothelial markers, VCAM1, E-selectin, and VEGFA. However, post hoc analyses showed that our study was statistically underpowered for these outcomes.

Conventional antipsychotic medication is ineffective in around a third of patients with schizophrenia, and the nature of the therapeutic response is unpredictable. We investigated whether response to antipsychotics is related to brain glutamate levels prior to treatment. Proton magnetic resonance spectroscopy was used to measure glutamate levels (Glu/Cr) in the anterior cingulate cortex (ACC) and in the thalamus in antipsychotic-naive or minimally medicated patients with first episode psychosis (FEP, n = 71) and healthy volunteers (n = 60), at three sites. Following scanning, patients were treated with amisulpride for 4 weeks (n = 65), then 1H-MRS was repeated (n = 46). Remission status was defined in terms of Positive and Negative Syndrome Scale for Schizophrenia (PANSS) scores. Higher levels of Glu/Cr in the ACC were associated with more severe symptoms at presentation and a lower likelihood of being in remission at 4 weeks (P

IntroductionAbnormalities within hypothalamus-pituitary-adrenal (HPA) axis might interact with other neurobiological systems to enhance the risk of psychosis. Most of the neurodevelopmental and HPA axis changes occur in adolescence; this is also the period when prodromal and psychotic symptoms occur for the first time. More knowledge about how various stress components interact can advance understanding of the link between psychosis and the HPA axis.MethodWe examined 41 ultra high-risk (UHR) patients and 40 antipsychotic-naïve first-episode schizophrenia (FES) patients and compared them with 47 matched controls. The Perceived Stress Scale and the Recent Life Events Questionnaire were used to assess the stress levels. Day-time saliva samples were taken to measure cortisol. The pituitary gland volume was measured manually on the structural MRI using stereology.ResultsOnly the UHR patients, had a higher cortisol increase just after awakening (p = 0.009) compared to healthy controls. In UHR patients, we found a negative correlation between cortisol increase after awakening and symptom severity (p = 0.008). Pituitary gland volume and diurnal cortisol were not significantly different among the three groups. There was no correlation between pituitary gland volume, perceived stress/recent life events and any of the cortisol measures or symptoms.ConclusionSymptom severity during the very early phase of illness (UHR) seems to be associated with altered cortisol increase. Longitudinal studies in UHR patients would be useful to examine how stress levels affect the course of the illness.

Objective Obstructive sleep apnea (OSA) is an independent risk factor for stroke. Little is known about the cerebrovascular hemodynamic changes during apnea. Hypercapnia occurs in apneas and hypopneas, and a reduced cerebral vasodilatory response to CO2 could compromise the cerebral blood flow (CBF). Therefore, we aimed to evaluate whether the apnea–hypopnea index (AHI) affected the cerebrovascular response to CO2. Methods A total of 11 patients with OSA were compared to 16 controls. We assessed the cerebrovascular responses with arterial spin labeling (ASL) and blood oxygen level-dependent (BOLD) magnetic resonance imaging during hypercapnia or breath-holding tasks. Results The CBF response to CO2 was impaired with increasing AHI (average CBF: p = 0.018; gray matter: p = 0.038; white matter: p = 0.045), that is, increased OSA severity. When comparing the OSA patients to the control subjects, the OSA patients had a significantly reduced CO2 response of the white matter CBF (p = 0.04). However, the BOLD response to CO2 and the breath-holding task did not show any significant differences between OSA patients and control subjects. Conclusion The cerebrovascular CO2 reactivity, measured by the CBF, was impaired with increasing AHI, that is, OSA severity. These findings may add to the understanding of the increased stroke risk found in OSA patients.

Negative symptoms (NS) are a central part of the symptomatology of schizophrenia, which is highly correlated to the functional outcome. Disturbances of the brain reward system are suggested to be central in the pathogenesis of NS by decreasing motivation and hedonic experiences. In this study, we compared reward-related brain activity in patients improving and not improving in NS after treatment with amisulpride.Thirty-nine antipsychotic-naive patients and 49 healthy controls completed functional magnetic resonance imaging with a modified monetary incentive delay task. Psychopathology of the patients was characterised with Positive and Negative Syndrome Scale (PANSS), and they were treated with individual doses of amisulpride (mean 271 mg) for 6 weeks, after which the examinations were repeated.Patients improved on positive, general, and total PANSS score after treatment ( P.001). Fourteen patients had ≥20% improvement of NS, whereas 25 patients improved20%. At baseline, one-way analysis of variance showed group difference bilaterally in the caudate nucleus and in the right nucleus accumbens (all P.002), which was caused by decreased reward anticipation activity in the nonimproving patients compared to healthy controls. There was a significant group × time interaction, with the healthy controls and the improvers decreasing and the nonimprovers increasing in reward anticipation activity after treatment, most pronounced in the left caudate nucleus ( P = .001).Patients improving in NS score had a less aberrant reward system at baseline, but reward related activity was reduced over time. Patients not improving in NS showed decreased striatal reward-activity at baseline, which improved over time. Whether this is associated with alteration in working memory and reward learning or with pronounced symptoms within specific domains of NS may be addressed in future studies.

BackgroundIndividuals at ultra-high-risk (UHR) for psychosis present with emerging symptoms and decline in functioning. Previous univariate analyses have indicated widespread white matter (WM) aberrations in multiple brain regions in UHR individuals and patients with schizophrenia. Using multivariate statistics, we investigated whole brain WM microstructure and associations between WM, clinical symptoms, and level of functioning in UHR individuals.MethodsForty-five UHR individuals and 45 matched healthy controls (HCs) underwent magnetic resonance diffusion tensor imaging (DTI) at 3 Tesla. UHR individuals were assessed with the Comprehensive Assessment of At-Risk Mental States, Scale for the Assessment of Negative Symptoms, and Social and Occupational Functioning Assessment Scale. Partial least-squares correlation analysis (PLSC) was used as statistical method.ResultsPLSC group comparisons revealed one significant latent variable (LV) accounting for 52% of the cross-block covariance. This LV indicated a pattern of lower fractional anisotropy (FA), axial diffusivity (AD), and mode of anisotropy (MO) concomitant with higher radial diffusivity (RD) in widespread brain regions in UHR individuals compared with HCs. Within UHR individuals, PLSC revealed five significant LVs associated with symptoms and level of functioning. The first LV accounted for 31% of the cross-block covariance and indicated a pattern where higher symptom score and lower level of functioning correlated to lower FA, AD, MO, and higher RD.ConclusionsUHR individuals demonstrate complex brain patterns of WM abnormalities. Despite the subtle psychopathology of UHR individuals, aberrations in WM appear associated with positive and negative symptoms as well as level of functioning.

Background Cerebral small vessel disease is a common cause of vascular cognitive impairment in older people, with no licensed treatment. Cerebral blood flow is reduced in small vessel disease. Tadalafil is a widely prescribed phosphodiesterase-5 inhibitor that increases blood flow in other vascular territories. The aim of this trial is to test the hypothesis that tadalafil increases cerebral blood flow in older people with small vessel disease. Methods/design Perfusion by Arterial Spin labelling following Single dose Tadalafil In Small vessel disease (PASTIS) is a phase II randomised double-blind crossover trial. In two visits, 7-30 days apart, participants undergo arterial spin labelling to measure cerebral blood flow and a battery of cognitive tests, pre- and post-dosing with oral tadalafil (20 mg) or placebo. Sample size: 54 participants are required to detect a 15% increase in cerebral blood flow in subcortical white matter (p

The neurological disturbances of migraine aura are caused by transient cortical dysfunction due to waves of spreading depolarization that disrupt neuronal signaling. The effects of these cortical events on intrinsic brain connectivity during attacks of migraine aura have not previously been investigated. Studies of spontaneous migraine attacks are notoriously challenging due to their unpredictable nature and patient discomfort. We investigated 16 migraine patients with visual aura during attacks and in the attack-free state using resting state fMRI. We applied a hypothesis-driven seed-based approach focusing on cortical visual areas and areas involved in migraine pain, and a data-driven independent component analysis approach to detect changes in intrinsic brain signaling during attacks. In addition, we performed the analyses after mirroring the MRI data according to the side of perceived aura symptoms. We found a marked increase in connectivity during attacks between the left pons and the left primary somatosensory cortex including the head and face somatotopic areas (peak voxel: P = 0.0096, (x, y, z) = (-54, -32, 32), corresponding well with the majority of patients reporting right-sided pain. For aura-side normalized data, we found increased connectivity during attacks between visual area V5 and the lower middle frontal gyrus in the symptomatic hemisphere (peak voxel: P = 0.0194, (x, y, z) = (40, 40, 12). The present study provides evidence of altered intrinsic brain connectivity during attacks of migraine with aura, which may reflect consequences of cortical spreading depression, suggesting a link between aura and headache mechanisms. Hum Brain Mapp 38:2635-2642, 2017. © 2017 Wiley Periodicals, Inc.

Background Prediction error is the mismatch between expected and obtained outcome, and psychosis has been linked to aberrant striatal prediction error signal. Several lines of evidence indicate alterations of the glutamatergic system to be involved in the pathophysiology of schizophrenia. We have previously reported abnormal thalamic glutamate levels at illness onset in schizophrenia patients driven by increased levels in non-responding patients, and that glutamatergic levels in the thalamus in twins dis- or concordant for psychosis were heritable and associated with the illness. Glutamatergic abnormalities may affect processing of prediction error; however, it remains unresolved if prediction error is affected by antipsychotic treatment, and to which extend treatment effect on prediction error is predicted by glutamatergic levels in patients characterized as responders or non-responders. Here, we explore treatment effects of aripiprazole on striatal prediction error signal in initially antipsychotic-naïve patients characterized as responders and non-responders and relate the findings to thalamic glutamate levels. We hypothesize a different treatment response in prediction error signal in responders and non-responders, and an association to baseline glutamate levels. Methods Thirty-three patients (age 22 ± 4 years) and 33 healthy controls (HC) matched on age and gender underwent functional Magnetic Resonance imaging (fMRI) and magnetic resonance spectroscopy (1H-MRS) (3T) at baseline and after 6 weeks of treatment with aripiprazole. Prediction error related brain activity was examined using a Monetary Incentive Delay Task. Glutamate levels were estimated in the left thalamus and analyzed using LCModel. In patients, symptom severity was assessed with the Positive and Negative Syndrome Scale. The Andreasen criteria defined responders (N=10) and non- responders (N=23). Repeated measures analysis of variance was used to test the effect of time in prediction error signal with group (responders vs non-responders vs HC) as between subject factor and time as within factor. Analysis of variance, two sample t-test and paired sample t-test evaluated group differences at baseline and follow up. In a multiple regression analyses we investigated the influence of baseline glutamate levels, symptom severity and p-aripiprazole on changes in prediction error signal in both responders and non-responders. Results Repeated measures analysis of prediction error showed an effect of group (p=0.007) and no effect of time (p=0.29) or interaction (p=0.29). The effect of group was explained by an abnormal increased prediction error signal in responders (p=0.047) and non-responders (p=0.011) compared to HC at baseline, which was normalized at follow up in responders (p=0.94) but not in non-responders (p=0.02) compared to HC. Changes in prediction error signal following treatment were predicted by glutamate levels in non-responders (p=0.03) but not in responders (p=0.85) whereas p-aripiprazole and symptom severity did not predict changes in prediction error signal (all p>0.05). Discussion The findings suggest that treatment with a partial dopamine agonist normalizes prediction error signal in patients characterized as responders. Thalamic glutamate seems to play a role in the neural coding of prediction error in patients characterized as non-responders, where increased levels of glutamate in the thalamus seems to predict a less pronounced changes in prediction error signal.

Background Decreased functional magnetic resonance (fMRI) signaling in ventral striatum during reward anticipation has been a consistent finding in unmedicated patients with schizophrenia. Antipsychotic medication may normalize this, which has been associated with improvement in psychotic symptoms. Whether this initial treatment response predict long term clinical outcome have not been examined previously. We here present unique data from a cohort of antipsychotic näive patients, who was examined before and after six weeks of antipsychotic monotherapy, and again after six years of naturalistic treatment. We hypothesized that improved reward related fMRI-signaling in striatum during initial treatment will be associated with less severe symptoms and a higher level of function after six years. Methods Antipsychotic-naïve, first episode patients with schizophrenia and matched healthy controls were examined at three timepoints: Baseline, after six weeks and after six years. During the first six weeks, patients were treated with a D2/3 antagonist, after which they switched to a naturalistic clinical setting. At all three timepoints, fMRI was obtained while participants played a monetary rewarding game. Mean contrast signal during anticipation of salient events was extracted from predefined regions of interest in nucleus accumbens and caudatus. Additionally, symptom severity and level of function were assessed in patients. Remission after six years was defined by the Andreasen criteria. Long term changes in patients were analyzed with paired t-test. Repeated measures ANOVA was used to compare fMRI signal in patients and controls over time. Changes in fMRI signal during the first six weeks was compared between remitted and unremitted patients with students t-test. Correlations between symptom severity, level of function and fMRI signal up were analyzed with Spearman or Pearson as appropriate. Results Long term follow-up data on fMRI and psychopathology was obtained from 25 patients and 28 controls 6.7 (4.3–8.7) years after baseline examinations. In patients, symptomatology and level of function was improved (all p Repeated measures ANOVA of the extracted fMRI contrast signal at baseline and six years showed a group*time interaction in left Nucleus accumbens (F=4.8, p= 0.038) and left caudatus (F= 4.08, p=0=049). Mean contrast signal increased in patients but decreased in healthy controls. Change in contrast signal in left caudatus during the first six weeks of treatment differed between remitted and non-remitted patients (t=2.2, p=0.044). An increase in signal during initial treatment was found in patients later being in remission, which was not observed in non-remitted patients. Decreased fMRI contrast signal in left caudatus at six years follow up was associated with a higher level of negative symptoms (r=-0.44, p=0.02) and a lower level of function (r=0.45, p=0.02). Discussion In this long-term follow up study, half of the patients were in remission 4–8 years after their first schizophrenia diagnosis. These individuals were characterized by a normalization of reward anticipation signaling in left striatal regions during their initial treatment with a selective D2/3 antagonist. Schizophrenia is a diagnosis with a heterogeneous outcome, and prognostic biomarkers are still missing. The present results suggest that normalization in reward processing during initial antipsychotic treatment may predict remission six years later. Although these results need to be reproduced, they do support the notion, that patients responding to antipsychotic treatment are characterized by changes in striatal function, which may be predictive for long-term outcome.

Data (attached) for a focused review and meta-analysis of cerebral levels of glutamate, Glx, and GABA levels assessed with 1H-MRS in high-risk of psychosis states was collected and stored at covidence.org and extracted to The Cochrane Collaboration Review Manager software package (RevMan Version 5.3) for meta-analytical purposes. Meta-analyses were performed with a random-effects, inverse-variance weighted model to calculate the pooled effect size. Heterogeneity was measured using the I2 value. Significance was assessed using two-sided 95% confidence intervals. Potential publication bias was assessed by visual inspection of funnel plots. Supplementary to the co-submitted article are comprehensive meta-analyses of glutamate, Glx, and GABA, as well as the PRISMA flow diagram of included studies and a list of studies included in the review along with available measures and methodological variables. The attached data offers an insight into the included studies and the specified metabolite values for each study and offers possible further investigation for other researchers, as well as an insight into the review and meta-analyses performed. The supplementary material also serves to support findings and interpretations in the main article.

Background Studies examining glutamate or gamma-aminobutyric acid (GABA) in ultra-high risk for psychosis (UHR) and the association with pathophysiology and cognition have shown conflicting results. We aimed to determine whether perturbed glutamate and GABA levels in the anterior cingulate cortex and glutamate levels in the left thalamus were present in UHR individuals and to investigate associations between metabolite levels and clinical symptoms and cognition. Methods We included 122 UHR individuals and 60 healthy control subjects. Participants underwent proton magnetic resonance spectroscopy to estimate glutamate and GABA levels and undertook clinical and cognitive assessments. Results We found no differences in metabolite levels between UHR individuals and healthy control subjects. In UHR individuals, we found negative correlations in the anterior cingulate cortex between the composite of glutamate and glutamine (Glx) and the Comprehensive Assessment of At-Risk Mental States composite score (p = .04) and between GABA and alogia (p = .01); positive associations in the anterior cingulate cortex between glutamate (p = .01) and Glx (p = .01) and spatial working memory and between glutamate (p = .04), Glx (p = .04), and GABA (p = .02) and set-shifting; and a positive association in the thalamus between glutamate and attention (p = .04). No associations between metabolites and clinical or cognitive scores were found in the healthy control subjects. Conclusions An association between glutamate and GABA levels and clinical symptoms and cognition found only in UHR individuals suggests a loss of the normal relationship between metabolite levels and cognitive function. Longitudinal studies with investigation of clinical and cognitive outcome and the association with baseline levels of glutamate and GABA could illuminate whether glutamatergic and GABAergic dysfunction predicts clinical outcome.

This study investigates the association between intelligence and brain power responses to a passive audiovisual stimulation. We measure the power of gamma-range steady-state responses (SSRs) as well as intelligence and other aspects of neurocognitive function in 40 healthy males born in 1953. The participants are a part of a Danish birth cohort study and the data therefore include additional information measured earlier in life. Our main power measure is the difference in power between a visual stimulation and a combined audiovisual stimulation. We hypothesize and establish empirically that the power measure is associated with intelligence. In particular, we find a highly significant correlation between the power measure and present intelligence scores. The association is robust to controlling for size-at-birth measures, length of education, speed of processing as well as a range of other potentially confounding factors. Interestingly, we find that intelligence scores measured earlier in life (childhood, youth, late midlife), are also correlated with the present-day power measure, suggesting a deep connection between intelligence and the power measure. Finally, we find that the power measure has a high sensitivity for detection of an intelligence score below the average.

BACKGROUND: Alterations of the brain reward system have been found in schizophrenia patients and prediction error coding has been suggested to underlie the formations of psychotic symptoms. Prediction errors are the discrepancy between what actually happens and what we expect to happen. This misprediction has been suggested to contribute to misallocation of attention leading to generation of psychotic symptoms. Recent data from our group have shown that thalamic glutamate levels are not only heritable and linked to liability for schizophrenia, but also increased in the thalamus at illness onset; the latter was driven by patients that subsequently did not respond to treatment. However, it remains unresolved if glutamatergic dysfunction is correlated to striatal reward processing and prediction errors. In the present study, we aim to explore the relationship between thalamic glutamate levels and striatal prediction error coding in psychosis before the patients first antipsychotic treatment. METHODS: 40 antipsychotic-naïve patients with first-episode psychosis (age 22.8±5.7, 15(38%) males) and 38 healthy controls matched on age and gender (age 21.8±3.2, 17(45%) males) underwent functional Magnetic Resonance imaging (fMRI) and magnetic resonance spectroscopy (1H-MRS) (3 Tesla scanner). The patients were moderately ill with a mean PANSS total score of 74 (15). Glutamate levels scaled to creatine was estimated using the PRESS sequence in a 2.0x1.5x2.0 cm voxel in the left thalamus and analyzed using LCModel. Reward related brain activity was examined using a Monetary Delay Task. Analyses were focused on evaluation of outcome during trials where the outcome was worse than expected indicating negative prediction error (miss-contrast). Tools from the FMRIB Software Library were used to extract ROI parameter estimates from the left nucleus caudatus. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). RESULTS: For reward related brain activity, significant group difference was observed in the miss-contrast (p=0.019) with patients having a higher contrast activity. For thalamic glutamate there was a trend towards higher levels in the patients (p=0.057). In patients, a significant negative correlation was observed between glutamate levels and activity in the miss-contrast (r=-0.41; p= 0.009), which was not present in healthy controls. There was no significant correlation between symptom severity and prediction error activity or glutamate levels. DISCUSSION: Our findings support that patients have aberrant prediction error signaling and increased thalamic glutamate levels. However, patients with increased thalamic glutamate levels display a more normal prediction error signaling, whereas patients with lower thalamic glutamate levels display abnormal prediction error signaling. This could suggest a role of thalamic glutamate in the neural coding of prediction errors in antipsychotic-naïve first-episode psychosis patients but not in healthy controls.

BACKGROUND: Regional cerebral blood flow (rCBF) has been found altered in the thalamus, frontal regions and the putamen of patients with schizophrenia. It is not known if these changes in rCBF are due to genetic influences, but findings of altered rCBF in first degree relatives of patients with schizophrenia (1) indicate a familial and possibly genetic influence. A study design including discordant monozygotic (MZ) and dizygotic (DZ) twins provides the possibility to estimate heritability and correlation to disease, and to infer if a correlation is influenced by genetic or environmental factors. Our hypothesis was that rCBF in the thalamus, the frontal lobes and the putamen would be heritable and altered in schizophrenia spectrum disorder (F2x.x), and that this correlation would be influenced by genetic factors. Additional similar analyses were performed limiting the sample to include only proband pairs with narrow schizophrenia (F20.x) and healthy controls. METHODS: We included 22 complete MZ and 20 complete DZ twin pairs concordant or discordant for schizophrenia spectrum disorder (ICD 10 F2x.x) and 27 complete MZ and 18 complete DZ healthy control pairs by linking The Danish Twin Register and The Danish Psychiatric Central Research Register. Twenty-five additional twins were analyzed without their siblings. rCBF was measured in the thalamus, the frontal lobes and the putamen with pseudo-continuous arterial spin-labeling on a 3 tesla magnetic resonance scanner, and structural equation modelling was used for twin statistics. RESULTS: We found rCBF in the frontal lobes to be heritable (h2=0.44, [0.22 – 0.60]), but there was no significant correlation to disease. In the left thalamus rCBF correlated to schizophrenia spectrum disorders (r=0.17, 95% CI [0.03 - 0.31]; p = 0.02), the same correlation was found in both the left (r=0.19, [0.05–0.32]; p=0.007) and the right putamen (r=0.18, [0.03–0.32]; p=0.02). When the sample was limited to schizophrenia (F20.x) patients only, we found significant shared genetic influences between rCBF in the left putamen and liability for schizophrenia (phenotypic correlation=0.44 [0.28–0.58], p

BACKGROUND: Schizophrenia is characterized by cognitive deficits persisting throughout the illness from the first episode. These deficits may be associated with disruptions in white matter (WM) connectivity. Steeper age-related reductions in WM have been found in schizophrenia patients compared to healthy controls (HC), but it is unclear if these reductions are mainly influenced by age of illness onset, duration of illness, or an interaction between the two. Previous longitudinal studies of WM microstructure (measured with fractional anisotropy) have predominantly investigated medicated patients at two time-points and follow-up periods are generally limited to months. We aim to examine the impact of age at inclusion (in patients defined as illness onset) and time since inclusion (in patients defined as illness duration) on white matter and cognition trajectories in schizophrenia compared to healthy controls. METHODS: We included 119 antipsychotic-naïve first-episode patients with an ICD-10 diagnosis of schizophrenia (mean age: 24,2 [18,2-42,6], 55 % men) and 111 matched HC (mean age: 24,2 [18,1-42,9], 54 % men) in a prospective longitudinal follow-up study. Patients and HC had completed between one and six visits with valid MRI and/or cognitive data. This resulted in a total of 791 visits (at inclusion, 6 weeks, 6 months, 1 year, 2 years, and 5–7 years). Subjects were scanned on a Philips 3T MRI scanner with a diffusion weighted sequence and examined with the Brief Assessment of Cognition in Schizophrenia (BACS). Outcome measures were mean fractional anisotropy (FA) and two cognitive measures: word fluency and processing speed. Using linear mixed models, we analyzed main effects and interaction effects of group, age at inclusion (age), time since inclusion (time), and time since inclusion squared (time^2) for FA, fluency, and processing speed, respectively. RESULTS: For processing speed, we found a main effect of group (p

BACKGROUND: Disturbances in the interacting dopaminergic, glutamatergic and GABAergic systems in the cortico-striato-thalamo-cortical circuits in the brain have been implicated in the pathophysiology of psychosis. Preclinical literature suggests that these disturbances are linked to each other, whereas recent clinical data have pointed to separate subgroups of patients characterized by either glutamatergic or dopaminergic abnormalities. In the present study we explore the associations between dopamine synthesis capacity and glutamate and GABA levels in antipsychotic-naïve first-episode psychosis (FEP) patients. METHODS: The study is ongoing. We have now processed magnetic resonance spectroscopy (MRS) and positron emission tomography (18F-FDOPA-PET) data on 22 patients (32% males, mean age 22 (±4.3)) and 18 controls (50% males, mean age 22 (±2.7)). All patients are strictly antipsychotic-naïve and have no substance abuse. The diagnosis is validated with a diagnostic interview. The patients fulfill the criteria for schizophrenia (n:15), non-organic psychosis (n:5), schizoaffective disorder (n:1) or paranoid psychosis (n:1). They are moderately ill with a mean total score of 78 (±9.6) on the Positive and Negative Syndrome Scale. Glutamate and GABA-levels in the anterior cingulate cortex (ACC) are obtained with MRS. Dopamine synthesis capacity in striatum is measured with 18F-FDOPA-PET. The mean dopamine synthesis capacity is extracted from the whole striatum. Additionally, striatal subregions are defined anatomically (nucleus accumbens, nucleus caudatus and putamen, left and right) and subregional dopamine synthesis capacities are obtained. The association between dopamine synthesis capacity and levels of glutamate and GABA in patients and controls is assessed with linear regression with dopamine synthesis capacity as dependent variable and group and GABA or glutamate as independent variables. Analyses are performed with and without adjustment for age and sex. RESULTS: High dopamine synthesis capacity in the total striatum is associated with low ACC glutamate levels in patients (p=.03), but not in controls. This association remains significant after adjusting for age and sex (p=.02). In all subjects, dopamine synthesis capacity in the left caudate is positively correlated with ACC GABA (p

Background: High-intensity interval training (HIIT) is superior to moderate-intensity continuous training in improving cardiorespiratory fitness in patients with cardiovascular disease, but is it safe, feasible and effective in patients with stroke? We investigated feasibility and effect of early, home-based HIIT in patients with lacunar stroke combined with usual care vs. usual care, only. Methods: Patients with minor stroke (severity: 55/58 point on the Scandinavian Stroke Scale) were randomized to HIIT or usual care in a randomized, controlled trial. We measured the following outcomes at baseline and post-intervention: cardiorespiratory fitness monitored as power output from the Graded Cycling Test with Talk Test (GCT-TT; primary outcome), physical activity, fatigue, depression, well-being, stress, cognition, endothelial function, blood pressure, body mass index, and biomarkers. Results: We included 71 patients (mean age 63.7 ± 9.2), 49 men, 31 in intervention group. Home-based HIIT was feasible with no reported adverse events in relation to the intervention. No significant change between the groups in GCT-TT power output was detected ( p = 0.90). The change in time spent on vigorous-intensity activity was 2 h/week and 0.6 h/week, intervention and usual care, respectively ( p = 0.045). There were no significant differences between groups in the remaining secondary outcomes. Conclusion: HIIT was feasible and safe in patients with lacunar stroke. Patients can engage early in home-based HIIT when involved in choosing exercise modality and guided by weekly motivational phone calls. Within 3 months, HIIT did, however, not yield effect on cardiorespiratory fitness. We await further evaluation of long-term effects of this intervention on continued regular physical exercise and cardiovascular event. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT02731235.

Research findings implicate cerebral glutamate in the pathophysiology of schizophrenia, including genetic studies reporting associations with glutamatergic neurotransmission. The extent to which aberrant glutamate levels can be explained by genetic factors is unknown, and if glutamate can serve as a marker of genetic susceptibility for schizophrenia remains to be established. We investigated the heritability of cerebral glutamate levels and whether a potential association with schizophrenia spectrum disorders could be explained by genetic factors. Twenty-three monozygotic (MZ) and 20 dizygotic (DZ) proband pairs con- or discordant for schizophrenia spectrum disorders, along with healthy control pairs (MZ = 28, DZ = 18) were recruited via the National Danish Twin Register and the Psychiatric Central Register (17 additional twins were scanned without their siblings). Glutamate levels in the left thalamus and the anterior cingulate cortex (ACC) were measured using 1[H]-magnetic resonance spectroscopy at 3 Tesla and analyzed by structural equation modeling. Glutamate levels in the left thalamus were heritable and positively correlated with liability for schizophrenia spectrum disorders (phenotypic correlation, 0.16, [0.02–0.29]; p = 0.010). The correlation was explained by common genes influencing both the levels of glutamate and liability for schizophrenia spectrum disorders. In the ACC, glutamate and glx levels were heritable, but not correlated to disease liability. Increases in thalamic glutamate levels found in schizophrenia spectrum disorders are explained by genetic influences related to the disease, and as such the measure could be a potential marker of genetic susceptibility, useful in early detection and stratification of patients with psychosis.

Background: High-intensity interval training (HIIT) is superior to moderate-intensity continuous training (MICE) in improving aerobic fitness in patients with cardiovascular disease. Few studies have investigated the effect of HIIT in patients with stroke and none specifically in patients with small vessel disease stroke (SVDS). Purpose: We aimed to investigate the short-term effect of 12-weeks home-based HIIT post stroke in addition to usual care, versus usual care only. Methods: We included 71 patients with SVDS in a randomised controlled trial, intervention vs. control 1:1. At baseline and after 3 months we assessed: aerobic fitness (power output from the Graded Cycling Test with Talk Test (GCT-TT)), physical activity, fatigue, depression, well-being, stress, cognition, endothelial function, blood pressure, body mass index, and blood biomarkers. Results: We found that the patients in the intervention group spent more time on vigorous-intensity activity than the usual care group. Home-based HIIT was feasible, with no adverse events reported. No significant difference was detected in GCT-TT power output between groups. Further, we found no significant differences between the groups in general well-being (depression, stress, fatigue, cognition, and quality of life). Insulin levels decreased slightly in the active group (p=0.048). Conclusion: Importantly, this study shows that patients with SVDS can engage in home-based HIIT when encouraged weekly by phone, and provided either a stationary bicycle or choosing a high intensity activity of their own interest. However, increased activity was not reflected in short-term effect on aerobic fitness. This may be due to a lower than requested intensity or duration of activity. We need more investigations on long-term effects, and how to further increase physical activity and aerobic fitness.

Background: The effects of physical exercise in patients with lacunar stroke, seem promising in secondary prevention and only few studies have investigated the effect of high-intensity interval training in patients with lacunar stroke. This study will be investigating whether high-intensity interval training improves cardiovascular fitness as well as cognitive- and endothelial function and potentially attenuating the risk of recurrent stroke. Methods: A randomized controlled trial evaluating 12 weeks of home-based, high-intensity interval training compared with usual care. The intervention group will be exercising 15 min a day, 5 days a week, for 12 weeks. Outcomes will be evaluated at baseline, three, six and twelve months post-stroke with ‘The Graded Cycling Test with Talk Test’ as the primary outcome registered as power output in Watts. Additionally, an annually register-based follow-up will be performed for 5 years from date of inclusion with a composite endpoint of cardiovascular disease or death. Secondary outcomes will be: physical activity, endothelial response, mental well-being, cognition, mood, fatigue, stress, and MRI scan. Discussion: This study is going to show if early initiated home-based high-intensity interval training is feasible and effective in patients with lacunar stroke. A self-chosen aerobic exercise modality allows a realistic implementation of practice, together with greater chance of long-term adherence. A limitation of the study is that recruitment bias cannot be ruled out, as there may be a preferential enrolment of patients who are self-motivated to engage in exercise. Keywords: High-intensity interval training, Lacunar stroke, Risk factors, Secondary prevention

Objectives: Long-term dopamine D-2/3 receptor blockade, common to all antipsychotics, may underlie progressive brain volume changes observed in patients with chronic schizophrenia. In the present study, we examined associations between cortical volume changes and extrastriatal dopamine D-2/3 receptor binding potentials (BPND) in first-episode schizophrenia patents at baseline and after antipsychotic treatment.Methods: Twenty-two initially antipsychotic-naive patients underwent magnetic resonance imaging (MRI), [I-123]epidepride single-photon emission computerised tomography (SPECT), and psychopathology assessments before and after 3 months of treatment with either risperidone (N=13) or zuclopenthixol (N=9). Twenty healthy controls matched on age, gender and parental socioeconomic status underwent baseline MRI and SPECT.Results: Neither extrastriatal D-2/3 receptor BPND at baseline, nor blockade at follow-up, was related to regional cortical volume changes. In post-hoc analyses excluding three patients with cannabis use we found that higher D-2/3 receptor occupancy was significantly associated with an increase in right frontal grey matter volume.Conclusions: The present data do not support an association between extrastriatal D-2/3 receptor blockade and extrastriatal grey matter loss in the early phases of schizophrenia. Although inconclusive, our exclusion of patients tested positive for cannabis use speaks to keeping attention to potential confounding factors in imaging studies.