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Background: Findings of reward disturbances in unaffected relatives of patients with schizophrenia suggest reward disturbances as an endophenotype for schizophrenia. Twin studies, where 1 twin has been diagnosed with a schizophrenia spectrum disorder, can further explore this. Methods: We used Danish registries to identify twin pairs with at least 1 twin having a schizophrenia spectrum disorder diagnosis and control twin pairs matched on age, sex, and zygosity. The analyses included data from 34 unaffected co-twins (16 females), 42 probands with schizophrenia spectrum disorder (17 females), and 83 control twins (42 females). Participants performed a modified incentive delay task during functional magnetic resonance imaging. Whole-brain group differences were analyzed by performing comparisons between co-twins and control twins. Correlations with cognitive flexibility were tested. Results: Compared with control twins, co-twins showed no differences in striatal regions, but increased signal in the dorsolateral prefrontal cortex (DLPFC) during missed target contrast was observed. In co-twins, increased DLPFC signal was associated with lower intra-extra dimensional set-shifting scores indicative of higher cognitive flexibility. Conclusions: Unaffected co-twins did not have decreased striatal activity during anticipation as previously reported for patients with schizophrenia. Instead, they showed increased activity in the DLPFC during evaluation of missed target contrast, which correlated with their level of cognitive flexibility. Unaffected co-twins had no diagnosis at a mean age of 40 years. This could indicate that greater cognitive flexibility and increased activity in the right DLPFC during processing of unexpected negative outcome represents a compensatory resilience mechanism in predisposed twins.

BackgroundDisturbances in presynaptic dopamine activity and levels of GABA (gamma-aminobutyric acid) and glutamate plus glutamine collectively may have a role in the pathophysiology of psychosis, although separately they are poor diagnostic markers. We tested whether these neurotransmitters in combination improve the distinction of antipsychotic-naïve patients with first-episode psychosis from healthy control subjects.MethodsWe included 23 patients (mean age 22.3 years, 9 male) and 20 control subjects (mean age 22.4 years, 8 male). We determined dopamine metabolism in the nucleus accumbens and striatum from 18F-fluorodopa (18F-FDOPA) positron emission tomography. We measured GABA levels in the anterior cingulate cortex (ACC) and glutamate plus glutamine levels in the ACC and left thalamus with 3T proton magnetic resonance spectroscopy. We used binominal logistic regression for unimodal prediction when we modeled neurotransmitters individually and for multimodal prediction when we combined the 3 neurotransmitters. We selected the best combination based on Akaike information criterion.ResultsIndividual neurotransmitters failed to predict group. Three triple neurotransmitter combinations significantly predicted group after Benjamini-Hochberg correction. The best model (Akaike information criterion 48.5) carried 93.5% of the cumulative model weight. It reached a classification accuracy of 83.7% (p = .003) and included dopamine synthesis capacity (Ki4p) in the nucleus accumbens (p = .664), GABA levels in the ACC (p = .019), glutamate plus glutamine levels in the thalamus (p = .678), and the interaction term Ki4p × GABA (p = .016).ConclusionsOur multimodal approach proved superior classification accuracy, implying that the pathophysiology of patients represents a combination of neurotransmitter disturbances rather than aberrations in a single neurotransmitter. Particularly aberrant interrelations between Ki4p in the nucleus accumbens and GABA values in the ACC appeared to contribute diagnostic information.

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: Brain structural alterations and cognitive dysfunction are independent predictors for poor clinical outcome in schizophrenia, and the associations between these domains remains unclear. We employed a novel, multiblock partial least squares correlation (MB-PLS-C) technique and investigated multivariate cortico-cognitive patterns in patients with treatment-resistant schizophrenia (TRS) and matched healthy controls (HC). Method: Forty-one TRS patients (age 38.5 ± 9.1, 30 males (M)), and 45 HC (age 40.2 ± 10.6, 29 M) underwent 3T structural MRI. Volumes of 68 brain regions and seven variables from CANTAB covering memory and executive domains were included. Univariate group differences were assessed, followed by the MB-PLS-C analyses to identify group-specific multivariate patterns of cortico-cognitive coupling. Supplementary three-group analyses, which included 23 non-affected first-degree relatives (NAR), were also conducted. Results: Univariate tests demonstrated that TRS patients showed impairments in all seven cognitive tasks and volume reductions in 12 cortical regions following Bonferroni correction. The MB-PLS-C analyses revealed two significant latent variables (LVs) explaining > 90% of the sum-of-squares variance. LV1 explained 78.86% of the sum-of-squares variance, describing a shared, widespread structure-cognitive pattern relevant to both TRS patients and HCs. In contrast, LV2 (13.47% of sum-of-squares variance explained) appeared specific to TRS and comprised a differential cortico-cognitive pattern including frontal and temporal lobes as well as paired associates learning (PAL) and intra-extra dimensional set shifting (IED). Three-group analyses also identified two significant LVs, with NARs more closely resembling healthy controls than TRS patients. Conclusions: MB-PLS-C analyses identified multivariate brain structural-cognitive patterns in the latent space that may provide a TRS signature.

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.

Background Various schizophrenic symptoms are suggested to be linked to a dysfunction of the brain reward system. Several studies have found alterations in the reward processing in patients with schizophrenia; however, most previous findings might be confounded by medication effects. Methods Thirty-one antipsychotic-naive schizophrenia patients and 31 age- and gender-matched healthy control subjects were examined with functional magnetic resonance imaging while playing a variant of the monetary incentive delay task. The task variant made it possible to separate overall salience (defined as arousing events) into behavioral salience (events where a predicted reward requires performance) and valence anticipation (the anticipation of a monetarily significant outcome) . Furthermore, the evaluation of monetary gain and loss was assessed. Results During reward anticipation, patients had a significant attenuation of the activation in ventral tegmentum, ventral striatum, and anterior cingulate cortex during presentation of salient cues. This signal attenuation in ventral striatum was correlated with the degree of positive symptoms. Signal attenuation was most pronounced for behavioral salience and nonsignificant for value anticipation. Furthermore, patients showed a changed activation pattern during outcome evaluation in right prefrontal cortex. Conclusion Our results suggest that changes during reward anticipation in schizophrenia are present from the beginning of the disease. This supports a possible involvement of reward disturbances in the pathophysiology of schizophrenia. The most pronounced changes were seen in relation to overall salience. In ventral striatum these changes were associated with the degree of positive symptoms.

Visual neglect and extinction are well-known effects of lesions in the right hemisphere. This study shows that even with minor or no clinical signs of these deficits, and in the stable phase of recovery, asymmetric visual perception is common after right side lesions. Whole, partial and colour report experiments were used to estimate psychophysical parameters related to visual capacity and attentional weighting in 26 patients with stroke in the right side of the brain. The results were analyzed using Bundesen's Theory of Visual Attention (TVA [Bundesen, C. (1990). A theory of visual attention. Psychological Review, 97, 523-547]) including bootstrap estimation of the measurement error related to each test result [Habekost, T., & Bundesen, C. (2003). Patient assessment based on a theory of visual attention (TVA): Subtle deficits after a right frontal-subcortical lesion. Neuropsychologia, 41, 1171-1188]. Lesions were examined by MR scanning and analyzed statistically. Two main types of deficit were found. The first type was related to perception of unilateral displays, where most patients showed left side reductions of visual processing speed. This visual asymmetry correlated with injury to the putamen and surrounding white matter. The second deficit type occurred with bilateral displays, which increased the visual asymmetry (extinction effect) for most patients with large cortico-subcortical lesions, but rarely for patients with focal lesions. However, in a single case with pulvinar damage, visual asymmetry occurred selectively with bilateral stimulation. Overall, the study provided an overview of the cognitive structure and lesion anatomy of subtle visual asymmetries after right side stroke.

Functional MRI (fMRI) carries the potential for non-invasive measurements of brain activity. Typically, what are referred to as activation images are actually thresholded statistical parametric maps. These maps possess large inter-session variability. This is especially problematic when applying fMRI to pre-surgical planning because of a higher requirement for intra-subject precision. The purpose of this study was to investigate the impact of residual movement artefacts on intra-subject and inter-subject variability in the observed fMRI activation. Ten subjects were examined using three different word-generation tasks. Two of the subjects were examined 10 times on 10 different days using the same paradigms. We systematically investigated one approach of correcting for residual movement effects: the inclusion of regressors describing movement-related effects in the design matrix of a General Linear Model (GLM). The data were analysed with and without modeling the residual movement artefacts and the impact on inter-session variance was assessed using F-contrasts. Inclusion of motion parameters in the analysis significantly reduced both the intra-subject as well as the inter-subject-variance.

The object of the present study was to compare stereological estimates of brain volumes obtained in vivo by magnetic resonance imaging (MRI) to corresponding volumes from physical sections in vitro. Brains of ten domestic pigs were imaged using a 3-T scanner. The volumes of different brain compartments were obtained from MR images by two observers and from physical sections using the Cavalieri estimator in combination with point counting. Paired t tests revealed no significant differences between the two methods for any of the five compartments considered, except for the basal gray compartment. However, although intraobserver difference of MRI estimates was acceptable, the interobserver difference was not. A statistical highly significant difference of 11-41% was observed between observers for volume estimates of all compartments considered. The study demonstrates that quantitative MRI is susceptible to observer dependent interpretation of images.

The purpose of this study was to establish the relationship between regional CBF and CBV at normal, resting cerebral metabolic rates. Eleven healthy volunteers were investigated with PET during baseline conditions, and during hyper- and hypocapnia. Values for rCBF and rCBV were obtained using 15O-labelled water and carbon monoxide, respectively. The mean value of rCBF using PET was 62 +/- 18 ml 100 g(-1) min(-1) during baseline conditions, with an average increase of 46% during hypercapnia, and a decrease of 29% during hypocapnia; baseline rCBV was 7.7 ml/100 g, with 27% increase during hypercapnia and no significant decrease during hypocapnia. A regionally uniform exponential relationship was confirmed between PaCO2 and rCBF as well as rCBV. It is shown that the theoretical implication of this is that the rCBV vs. rCBF relationship should be modelled by a power function; however, due to pronounced intersubject variability, the goodness of fit for linear and nonlinear models were not significantly different. The results of the study are applied to a numerical estimation of regional brain deoxy-haemoglobin content. Independently of the choice of model for the rCBV vs. rCBF relationship, a nonlinear deoxy-haemoglobin vs. rCBF relationship was predicted, and the implications for the BOLD response are discussed.

Cerebral blood flow (CBF), volume (CBV), and glucose consumption (CMRglc) are variables that undergo modulation by both physiological and pathophysiological alterations. For small changes in arterial pCO2, e.g., CBF changes approx. by 30% and CBV by 15% per kPa change in arterial pCO2. Quantification of regional CMRglc using positron emission tomography and 18F-fluorodeoxyglucose (PET-FDG) requires knowledge of the correction factor between FDG and glucose net clearances, the lumped constant (LC). Recent reevaluations have convincingly demonstrated that the correct value of LC is higher than the usually applied value, in the order of 0.8 instead of 0.5. In starvation, the human brain derives an increasing amount of its energy demand from ketone bodies as their blood level increases during fasting. This adaptative shift in fuel consumption also occurs with acute hyperketonemia. Hyperinsulinemia does not alter the overall CMRglc but it alters the brain glucose distribution and consequences for estimation of CMRglc by PET-FDG are discussed. Finally, in acute or chronic hyperglycemia there is no substantial evidence for changes in blood–brain barrier glucose transport capacity or CMRglc, whereas LC changes. The assessment of the implications of normal physiological variations underscores the caution with which findings in various pathophysiological conditions are interpreted.

Objective This research investigated the association between intelligence test scores and gamma-range steady-state power-responses (SS-PR) to an auditory, a visual, and a combined audiovisual stimulation. We hypothesized, and established empirically, that the difference in SS-PR from the mono-modal to the bimodal stimulation ( Δ P) is associated with intelligence. Methods We measured SS-PR as well as intelligence and other aspects of neurocognitive function in 36 healthy males born in 1953 who were a part of a Danish birth cohort study. Results We found a highly significant correlation between intelligence and the difference in SS-PR from the mono-modal to the bimodal stimulation ( Δ P). The findings were robust to controlling for size-at-birth measures, length of education, speed of processing as well as a range of other potentially confounding biomarkers. Interestingly, we found that intelligence scores measured at earlier points in time, namely in childhood, youth, and late midlife, also were significantly associated with Δ P. Finally, we found that Δ P has a sensitivity of 81% of detection of an intelligence score below the average. Discussion Our findings suggest that the uncovered relationship between intelligence and Δ P represents a constitutive relationship. Furthermore, our results are consistent with the notion that intelligence is related to the efficiency of the brain, and provide support for Haier’s efficiency hypothesis. Conclusion Δ P reflects intelligence throughougt life. Significance Our results indicate that Δ P may be useful as a supplement to cognitive neuropsychological testing.

Previous fMRI studies of the cerebrovascular response to hypercapnia have shown signal change in cerebral gray matter, but not in white matter. Therefore, the objective of the present study was to compare (15)O PET and T *(2)-weighted MRI during a hypercapnic challenge. The measurements were performed under similar conditions of hypercapnia, which were induced by inhalation of 5 or 7% CO(2). The baseline rCBF values were 65.1 ml hg(-1) min(-1) for temporal gray matter and 28.7 ml hg(-1) min(-1) for white matter. By linear regression, the increases in rCBF during hypercapnia were 23.0 and 7. 2 ml hg(-1) min(-1) kPa(-1) for gray and white matter. The signal changes were 6.9 and 1.9% for the FLASH sequence and were 3.8 and 1. 7% for the EPI sequence at comparable echo times. The regional differences in percentage signal change were significantly reduced when normalized by regional flow values. A deconvolution analysis is introduced to model the relation between fMRI signal and end-expiratory CO(2) level. Temporal parameters, such as mean transit time, were derived from this analysis and suggested a slower response in white matter than in gray matter regions. It was concluded that the differences in the magnitude of the fMRI response can largely be attributed to differences in flow and that there is a considerable difference in the time course of the response between gray and white matter.

WCN 2013 No: 2405 Topic: 7 Neuromuscular disorders Low and high frequency repetitive nerve stimulation in the diagnosis of myasthenia gravis N. Kvirkvelia, N.Mikava, R. Nikolaishvili, M. Jibladze, T. Akhvlediani, R. Shakarishvili. Department of Neurology and Neurosurgery, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia; Sarajishvili Institute of Clinical Neurology and Neurosurgery, Tbilisi, Georgia; Neurology Department, Khechinashvili University Clinic, Georgia; Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia Background: Diagnosis of myasthenia gravis (MG) typically is made based on patient's history and clinical findings. However, the diagnosis must be verified by the electrophysiological investigation of neuro-muscular transmission. The repetitive nerve stimulation (RNS) is an electrodiagnostic technique used to assess the efficacy of neuromuscular transmission. Objective: The objective of this study was to evaluate combined muscle action potential (CMAP) changes in response to high and low frequency rates of RNS in patients with MG. Patients and methods: The correlation of muscle strength and CMAP changes were investigated in 104 myasthenic patients. The muscle strength was graded on a scale from 0 to 5. Two stimulating parameters were used throughout the experiments — the low frequency stimulation (LFS) and high frequency stimulation (HFS). Results: It was found that in 15% of muscles with clinically detectable weakness the CMAP amplitudewas decreased, by 21% in area, and by8% in duration of the negative phase. The positive correlation was observed between the negative phase of CMAP and the muscle strength and negative correlation was observed between the negative phase duration and the muscle strength. Conclusion:We used RNS in a large cohort of patients as an additional tool for the confirmation of the MG diagnosis. We registered higher decrement in larger muscle groups which are more commonly affected clinically. However, smaller muscles, such as the abductor digiti quinti muscle are often preferable to investigate, because they create less discomfort for the patient and have fewer artifacts. doi:10.1016/j.jns.2013.07.1636 Abstract WCN 2013 No: 2277 Topic: 7 Neuromuscular disorders Altered somatosensory neurovascular coupling in patients with becker muscular dystrophy WCN 2013 No: 2277 Topic: 7 Neuromuscular disorders Altered somatosensory neurovascular coupling in patients with becker muscular dystrophy U. Lindberg, C. Kruuse, S. Joergensen, J. Vissing, N. Witting, E. Rostrup, H.B. Larsson. Functional Imaging Unit, Diagnostic Department, Glostrup Hospital, University of Copenhagen, Denmark; Lundbeck Foundation Center for Neurovascular Signalling, Glostrup, Denmark; Neurology, Herlev Hospital, University of Copenhagen, Herlev, Denmark; Department Neurology, Rigshospitalet, University of Copenhagen, Kbh O, Denmark Background: In patients suffering from Becker muscular dystrophy (BMD) variable degrees of cognitive impairment have been reported in addition to the well-known muscular and cardiac symptoms. BMD is caused by mutations in the dystrophin gene, changing the cellular dystrophin complex and subsequent muscular blood flow. Few studies have addressed the mechanisms of cognitive impairment. Lack of dystrophin, however, causes secondary loss of vasoactive molecules such as nitric oxide, which is as an important player in brain vascular control. We hypothesised that dystrophin can be involved in neurovascular coupling and cerebral reactivity measured by functional MRI and EEG. Objective: To study the baseline electrophysiological and fMRI BOLDresponse to external somatosensory stimulation in BMD patients compared to age and sex-matched healthy controls. Patients and methods: 17 men (mean age 38.5, range 25–63) with BMD and 8 healthy sex matched controls were included. Functional MRI (fMRI, BOLD) (3T, Phillips) and EEG with evoked potentials were performed during a somatosensoric stimulation paradigm on the dominant median nerve. Results: BMD patients showed a significantly (p b 0.02) decreased electrophysiological adaptation together with a decreased (p b 0.01) BOLD-response in the primary somatosensory cortex when compared to healthy controls. Conclusion: The preliminary results suggest that patients with BMD have a fundamentally altered cerebral neurovascular coupling, which could impact cognitive function in BMD patients. doi:10.1016/j.jns.2013.07.1637 Abstract — WCN 2013 No: 2379 Topic: 7 — Neuromuscular disorders Two cases of POEMS syndrome: Initially misdiagnosed as CIDP WCN 2013 No: 2379 Topic: 7 — Neuromuscular disorders Two cases of POEMS syndrome: Initially misdiagnosed as CIDP O. Watanabe, K. Arimura, T. Nakamura, Y. Arimura, Y. Inamori, Y. Takata, K. Michizono, E. Matsuura, H. Takashima. Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan POEMS syndrome (also known as Crow-Fukase syndrome) is a serious systemic disease characterized by polyneuropathy, anasarca, skin lesions and associated with osteoclastic bone lesions and with M-proteinemia. The diagnosis of POEMS syndrome is made robust by finding increased serum vascular endothelial growth factor (VEGF) in addition to the combination of the mentioned characteristic manifestations. The diagnosis of advanced POEMS syndrome is not difficult when the combinations of characteristic manifestations are fulfilled. However, in the initial stages, only half of POEMS patients start with neuropathy. Neuropathy in POEMS syndrome is characterized by a subacute, progressive sensorimotor type of polyneuropathy with mixed features of demyelination and axonal degeneration. However, nerve conduction study (NCS) results of POEMS syndrome occasionally fulfill the electrophysiological criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), thus leading to the caveat of an often initial misdiagnosis of CIDP. We herein present two female patients with POEMS syndrome. Case 1: A 67-year-old woman was admitted to one university hospital with a 1.5-year history of progressive weakness and paraesthesia. Her weakness and paraesthesia initially affected his lower limbs, progressing within 2 months to her upper limbs. Case 2: A 24-year-old woman was admitted to another university hospital with a 2-month history of progressive paraesthesia and muscle weakness affecting her lower limbs. Both cases were electrophysiologically diagnosed as CIDP, then treated with intravenous Abstracts / Journal of the Neurological Sciences 333 (2013) e422–e480 e459