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Background and Hypothesis Abnormal thalamic nuclei volumes and their link to cognitive impairments have been observed in schizophrenia. However, whether and how this finding extends to the schizophrenia spectrum is unknown. We hypothesized a distinct pattern of aberrant thalamic nuclei volume across the spectrum and examined its potential associations with cognitive symptoms. Study Design We performed a FreeSurfer-based volumetry of T1-weighted brain MRIs from 137 healthy controls, 66 at-risk mental state (ARMS) subjects, 89 first-episode psychosis (FEP) individuals, and 126 patients with schizophrenia to estimate thalamic nuclei volumes of six nuclei groups (anterior, lateral, ventral, intralaminar, medial, and pulvinar). We used linear regression models, controlling for sex, age, and estimated total intracranial volume, both to compare thalamic nuclei volumes across groups and to investigate their associations with positive, negative, and cognitive symptoms. Study Results We observed significant volume alterations in medial and lateral thalamic nuclei. Medial nuclei displayed consistently reduced volumes across the spectrum compared to controls, while lower lateral nuclei volumes were only observed in schizophrenia. Whereas positive and negative symptoms were not associated with reduced nuclei volumes across all groups, higher cognitive scores were linked to lower volumes of medial nuclei in ARMS. In FEP, cognition was not linked to nuclei volumes. In schizophrenia, lower cognitive performance was associated with lower medial volumes. Conclusions Results demonstrate distinct thalamic nuclei volume reductions across the schizophrenia spectrum, with lower medial nuclei volumes linked to cognitive deficits in ARMS and schizophrenia. Data suggest a distinctive trajectory of thalamic nuclei abnormalities along the course of schizophrenia. [ABSTRACT FROM AUTHOR]

Background and Hypothesis The cholinergic system is altered in schizophrenia. Particularly, patients' volumes of basal-forebrain cholinergic nuclei (BFCN) are lower and correlated with attentional deficits. It is unclear, however, if and how BFCN changes and their link to cognitive symptoms extend across the schizophrenia spectrum, including individuals with at-risk mental state for psychosis (ARMS) or during first psychotic episode (FEP). Study Design To address this question, we assessed voxel-based morphometry (VBM) of structural magnetic resonance imaging data of anterior and posterior BFCN subclusters as well as symptom ratings, including cognitive, positive, and negative symptoms, in a large multi-site dataset (n = 4) comprising 68 ARMS subjects, 98 FEP patients (27 unmedicated and 71 medicated), 140 patients with established schizophrenia (SCZ; medicated), and 169 healthy controls. Results In SCZ, we found lower VBM measures for the anterior BFCN, which were associated with the anticholinergic burden of medication and correlated with patients' cognitive deficits. In contrast, we found larger VBM measures for the posterior BFCN in FEP, which were driven by unmedicated patients and correlated at-trend with cognitive deficits. We found no BFCN changes in ARMS. Altered VBM measures were not correlated with positive or negative symptoms. Conclusions Results demonstrate complex (posterior vs. anterior BFCN) and non-linear (larger vs. lower VBM) differences in BFCN across the schizophrenia spectrum, which are specifically associated both with medication, including its anticholinergic burden, and cognitive symptoms. Data suggest an altered trajectory of BFCN integrity in schizophrenia, influenced by medication and relevant for cognitive symptoms. [ABSTRACT FROM AUTHOR]

Negative symptoms, such as lack of motivation or social withdrawal, are highly prevalent and debilitating in patients with schizophrenia. Underlying mechanisms of negative symptoms are incompletely understood, thereby preventing the development of targeted treatments. We hypothesized that in patients with schizophrenia during psychotic remission, impaired influences of both model-based and model-free reward predictions on decision-making ('reward prediction influence', RPI) underlie negative symptoms. We focused on psychotic remission, because psychotic symptoms might confound reward-based decision-making. Moreover, we hypothesized that impaired model-based/model-free RPIs depend on alterations of both associative striatum dopamine synthesis and storage (DSS) and executive functioning. Both factors influence RPI in healthy subjects and are typically impaired in schizophrenia. Twenty-five patients with schizophrenia with pronounced negative symptoms during psychotic remission and 24 healthy controls were included in the study. Negative symptom severity was measured by the Positive and Negative Syndrome Scale negative subscale, model-based/model-free RPI by the two-stage decision task, associative striatum DSS by 18F-DOPA positron emission tomography and executive functioning by the symbol coding task. Model-free RPI was selectively reduced in patients and associated with negative symptom severity as well as with reduced associative striatum DSS (in patients only) and executive functions (both in patients and controls). In contrast, model-based RPI was not altered in patients. Results provide evidence for impaired model-free reward prediction influence as a mechanism for negative symptoms in schizophrenia as well as for reduced associative striatum dopamine and executive dysfunction as relevant factors. Data suggest potential treatment targets for patients with schizophrenia and pronounced negative symptoms. [ABSTRACT FROM AUTHOR]

Negative symptoms such as anhedonia and apathy are among the most debilitating manifestations of schizophrenia (SZ). Imaging studies have linked these symptoms to morphometric abnormalities in 2 brain regions implicated in reward and motivation: the orbitofrontal cortex (OFC) and striatum. Higher negative symptoms are generally associated with reduced OFC thickness, while higher apathy specifically maps to reduced striatal volume. However, it remains unclear whether these tissue losses are a consequence of chronic illness and its treatment or an underlying phenotypic trait. Here, we use multicentre magnetic resonance imaging data to investigate orbitofrontal-striatal abnormalities across the SZ spectrum from healthy populations with high schizotypy to unmedicated and medicated first-episode psychosis (FEP), and patients with chronic SZ. Putamen, caudate, accumbens volume, and OFC thickness were estimated from T1-weighted images acquired in all 3 diagnostic groups and controls from 4 sites (n = 337). Results were first established in 1 discovery dataset and replicated in 3 independent samples. There was a negative correlation between apathy and putamen/accumbens volume only in healthy individuals with schizotypy; however, medicated patients exhibited larger putamen volume, which appears to be a consequence of antipsychotic medications. The negative association between reduced OFC thickness and total negative symptoms also appeared to vary along the SZ spectrum, being significant only in FEP patients. In schizotypy, there was increased OFC thickness relative to controls. Our findings suggest that negative symptoms are associated with a temporal continuum of orbitofrontal-striatal abnormalities that may predate the occurrence of SZ. Thicker OFC in schizotypy may represent either compensatory or pathological mechanisms prior to the disease onset. [ABSTRACT FROM AUTHOR]

Aberrant dopamine function in the dorsal striatum and aberrant intrinsic functional connectivity (iFC) between distinct cortical networks and thalamic nuclei are among the most consistent large-scale brain imaging findings in schizophrenia. A pathophysiological link between these two alterations is suggested by theoretical models based on striatal dopamine's topographic modulation of cortico-thalamic connectivity within cortico-basal-ganglia-thalamic circuits. We hypothesized that aberrant striatal dopamine links topographically with aberrant cortico-thalamic iFC, i.e. aberrant associative striatum dopamine is associated with aberrant iFC between the salience network and thalamus, and aberrant sensorimotor striatum dopamine with aberrant iFC between the auditory-sensorimotor network and thalamus. Nineteen patients with schizophrenia during remission of psychotic symptoms and 19 age- and sex-comparable control subjects underwent simultaneous fluorodihydroxyphenyl-l-alanine PET (18F-DOPA-PET) and resting state functional MRI (rs-fMRI). The influx constant kicer based on 18F-DOPA-PET was used to measure striatal dopamine synthesis capacity; correlation coefficients between rs-fMRI time series of cortical networks and thalamic regions of interest were used to measure iFC. In the salience network-centred system, patients had reduced associative striatum dopamine synthesis capacity, which correlated positively with decreased salience network-mediodorsal-thalamus iFC. This correlation was present in both patients and healthy controls. In the auditory-sensorimotor network-centred system, patients had reduced sensorimotor striatum dopamine synthesis capacity, which correlated positively with increased auditory-sensorimotor network-ventrolateral-thalamus iFC. This correlation was present in patients only. Results demonstrate that reduced striatal dopamine synthesis capacity links topographically with cortico-thalamic intrinsic dysconnectivity in schizophrenia. Data suggest that aberrant striatal dopamine and cortico-thalamic dysconnectivity are pathophysiologically related within dopamine-modulated cortico-basal ganglia-thalamic circuits in schizophrenia. [ABSTRACT FROM AUTHOR]

The reduction of aversive emotions by a conspecific's presence—called social buffering—is a universal phenomenon in the mammalian world and a powerful form of human social emotion regulation. Animal and human studies on neural pathways underlying social buffering typically examined physiological reactions or regional brain activations. However, direct links between emotional and social stimuli, distinct neural processes and behavioural outcomes are still missing. Using data of 27 female participants, the current study delineated a large-scale process model of social buffering's neural underpinnings, connecting changes in neural activity to emotional behaviour by means of voxel-wise multilevel mediation analysis. Our results confirmed that three processes underlie human social buffering: (i) social support-related reduction of activity in the orbitofrontal cortex, ventromedial and dorsolateral prefrontal cortices, anterior and mid-cingulate; (ii) downregulation of aversive emotion-induced brain activity in the superficial cortex-like amygdala and mediodorsal thalamus; and (iii) downregulation of reported aversive feelings. Results of the current study provide evidence for a distinct neural process model of aversive emotion regulation in humans by social buffering. [ABSTRACT FROM AUTHOR]

Background and Objectives Theoretical models propose the environment as a factor influencing the quality of life (QoL) of nursing home residents with dementia. This study investigates whether the observed QoL differs depending on the type of care unit. Research Design and Methods DemenzMonitor is an exploratory, observational study involving annual data collection in German nursing homes (2012–2014). For this analysis, we selected residents with a recorded diagnosis of dementia and severe cognitive impairment. QoL was measured with the proxy assessment QUALIDEM. Four care unit types were investigated: large integrated, large segregated, small integrated, and small segregated. Results We did not find a significant difference between the care units. During the 2 years, the observed QoL was not affected by any of the care unit types in a statistically significant or clinically relevant manner. However, a significant interaction effect between time and care unit types was found. Discussion and Implications Structural and organizational characteristics of care units, which in turn have implications for residents characteristics and the quality of care, may influence the QoL of residents. This may explain the interaction we observed. [ABSTRACT FROM AUTHOR]

While there is consistent evidence for increased presynaptic dopamine synthesis capacity in the striatum of patients with schizophrenia during psychosis, it is unclear whether this also holds for patients during psychotic remission. This study investigates whether striatal dopamine synthesis capacity is altered in patients with schizophrenia during symptomatic remission of positive symptoms, and whether potential alterations relate to symptoms other than positive, such as cognitive difficulties. Twenty-three patients with schizophrenia in symptomatic remission of positive symptoms according to Andreasen, and 24 healthy controls underwent 18F-DOPA-PET and behavioural-cognitive assessment. Imaging data were analysed with voxel-wise Patlak modelling with cerebellum as reference region, resulting in the influx constant kicer reflecting dopamine synthesis capacity. For the whole striatum and its subdivisions (i.e. limbic, associative, and sensorimotor), averaged regional kicer values were calculated, compared across groups, and correlated with behavioural-cognitive scores, including a mediation analysis. Patients had negative symptoms (Positive and Negative Syndrome Scale-negative 14.13 ± 5.91) and cognitive difficulties, i.e. they performed worse than controls in Trail-Making-Test-B (TMT-B; P = 0.01). Furthermore, kicer was reduced in patients for whole striatum (P = 0.004) and associative (P = 0.002) and sensorimotor subdivisions (P = 0.007). In patients, whole striatum kicer was negatively correlated with TMT-B (rho = -0.42, P = 0.04; i.e. the lower striatal kicer, the worse the cognitive performance). Mediation analysis showed that striatal kicer mediated the group difference in TMT-B. Results demonstrate that patients with schizophrenia in symptomatic remission of positive symptoms have decreased striatal dopamine synthesis capacity, which mediates the disorder's impact on cognitive difficulties. Data suggest that striatal dopamine dysfunction contributes to cognitive difficulties in schizophrenia. [ABSTRACT FROM AUTHOR]

Gyrification is a hallmark of human brain development, starting in the second half of gestation in primary cortices, followed by unimodal and then transmodal associative cortices. Alterations in gyrification have been noted in premature-born newborns and children, suggesting abnormal cortical folding to be a permanent feature of prematurity. Furthermore, both gyrification and prematurity are tightly linked with cognitive performance, indicating a link between prematurity, gyrification, and cognitive performance. To investigate this triangular relation, we tested the following two hypotheses: (i) gyrification is aberrant in premature-born adults; and (ii) aberrant gyrification contributes to the impact of prematurity on adult cognitive performance. One hundred and one very premature-born adults (i.e. adults born before 32 weeks of gestation, and/or with birth weight <1500 g) and 111 mature-born adults were assessed by structural MRI and cognitive testing at 27 years of age. Gyrification was measured by local cortical absolute mean curvature (AMC), evaluated through structural MRI. Cognitive performance was assessed by the Wechsler Adult Intelligence Scale, full-scale IQ test. Two-sample t-tests, regression and mediation analyses were used to assess AMC group differences and the relation between AMC, birth-related variables, and full-scale IQ. Three key findings were identified. First, local AMC was widely increased in fronto-temporo-parietal primary and associative cortices of very premature-born adults. Increase of AMC was inversely associated with gestational age and birth weight and positively associated with medical complications at birth, respectively. Second, increased AMC of temporal associative cortices specifically contributed to the association between prematurity and reduced adult IQ (two-path mediation), indicating that aberrant gyrification of temporal associative cortices is critical for impaired cognitive performance after premature birth. Finally, further investigation of the relationship of gyrification between the early folding postcentral cortices and associative temporal cortices, folding later during neurodevelopment, revealed that the effect of gyrification abnormalities in associative temporal cortices on adult IQ is influenced itself by gyrification abnormalities occurring in the early folding postcentral cortices (three-path mediation). These results indicate that gyrification development across cortical areas in the brain conveys prematurity effects on adult IQ. Overall, these results provide evidence that premature birth leads to permanently aberrant gyrification patterns suggesting an altered neurodevelopmental trajectory. Statistical mediation modelling suggests that both aberrant gyrification itself as well as its propagation across the cortex express aspects of impaired neurodevelopment after premature birth and lead to reduced cognitive performance in adulthood. Thus, markers of gyrification appear as potential candidates for prognosis and treatment of prematurity effects. [ABSTRACT FROM AUTHOR]

Posterior cortical atrophy is dominated by progressive degradation of parieto-occipital grey and white matter, and represents in most cases a variant of Alzheimer's disease. Patients with posterior cortical atrophy are characterized by increasing higher visual and visuo-spatial impairments. In particular, a key symptom of posterior cortical atrophy is simultanagnosia i.e. the inability to perceive multiple visual objects at the same time. Two neuro-cognitive mechanisms have been suggested to underlie simultanagnosia, either reduced visual short-term memory capacity or decreased visual processing speed possibly resulting from white matter impairments over and above damage to cortical brain areas. To test these distinct hypotheses, we investigated a group of 12 patients suffering from posterior cortical atrophy with homogenous lesion sides in parieto-occipital cortices and varying severity of grey and white matter loss. More specifically, we (i) tested whether impaired short-term memory capacity or processing speed underlie symptoms of simultanagnosia; (ii) assessed the link to grey and white matter damage; and (iii) integrated those findings into a neuro-cognitive model of simultanagnosia in patients with posterior cortical atrophy. To this end, simultaneous perception of multiple visual objects was tested in patients with posterior cortical atrophy mostly with positive Alzheimer's disease biomarkers and healthy age-matched controls. Critical outcome measures were identification of overlapping relative to non-overlapping figures and visuo-spatial performance in tests sensitive to simultanagnosia. Using whole report of briefly presented letter arrays based on the mathematically formulated 'Theory of Visual Attention', we furthermore quantified parameters of visual short-term memory capacity and visual processing speed. Grey and white matter atrophy was assessed by voxel-based morphometry analyses of structural magnetic resonance data. All patients showed severe deficits of simultaneous perception. Compared to controls, we observed a specific slowing of visual processing speed, while visual short-term memory capacity was preserved. In a regression analysis, processing speed was identified as the only significant predictor of simultaneous perception deficits that explained a high degree of variance (70-82%) across simultanagnosia tasks. More severe slowing was also indicative for more severe impairments in reading and scene comprehension. Voxel-based morphometry yielded extensive reductions of grey and white matter in parietooccipital and thalamic brain areas. Importantly, the degree of individual atrophy of white matter in left superior parietal lobe, but not of any grey matter region, was associated with processing speed. Based on these findings, we propose that atrophy of white matter commonly observed in posterior cortical atrophy leads to slowing of visual processing speed, which underlies the overt clinical symptoms of simultanagnosia. [ABSTRACT FROM AUTHOR]

There is striking overlap between the spatial distribution of amyloid-β pathology in patients with Alzheimer's disease and the spatial distribution of high intrinsic functional connectivity in healthy persons. This overlap suggests a mechanistic link between amyloid-β and intrinsic connectivity, and indeed there is evidence in patients for the detrimental effects of amyloid-β plaque accumulation on intrinsic connectivity in areas of high connectivity in heteromodal hubs, and particularly in the default mode network. However, the observed spatial extent of amyloid-β exceeds these tightly circumscribed areas, suggesting that previous studies may have underestimated the negative impact of amyloid-β on intrinsic connectivity. We hypothesized that the known positive baseline correlation between patterns of amyloid-β and intrinsic connectivity may mask the larger extent of the negative effects of amyloid-β on connectivity. Crucially, a test of this hypothesis requires the within-patient comparison of intrinsic connectivity and amyloid-β distributions. Here we compared spatial patterns of amyloid-β-plaques (measured by Pittsburgh compound B positron emission tomography) and intrinsic functional connectivity (measured by resting-state functional magnetic resonance imaging) in patients with prodromal Alzheimer's disease via spatial correlations in intrinsic networks covering fronto-parietal heteromodal cortices. At the global network level, we found that amyloid-β and intrinsic connectivity patterns were positively correlated in the default mode and several fronto-parietal attention networks, confirming that amyloid-β aggregates in areas of high intrinsic connectivity on a within-network basis. Further, we saw an internetwork gradient of the magnitude of correlation that depended on network plaque-load. After accounting for this globally positive correlation, local amyloid-β-plaque concentration in regions of high connectivity co-varied negatively with intrinsic connectivity, indicating that amyloid-β pathology adversely reduces connectivity anywhere in an affected network as a function of local amyloid-β-plaque concentration. The local negative association between amyloid-β and intrinsic connectivity was much more pronounced than conventional group comparisons of intrinsic connectivity would suggest. Our findings indicate that the negative impact of amyloid-β on intrinsic connectivity in heteromodal networks is underestimated by conventional analyses. Moreover, our results provide first within-patient evidence for correspondent patterns of amyloid-β and intrinsic connectivity, with the distribution of amyloid-β pathology following functional connectivity gradients within and across intrinsic networks. [ABSTRACT FROM AUTHOR]

Background: Human decision-making ranges between the extremes of automatic and fast model-free behavior (i.e., relying only on previous outcomes) and more flexible, but computationally demanding model-based behavior (i.e., implementing cognitive models). Model-based/model-free decision-making can be investigated using sequential decision tasks and has been shown to be associated with presynaptic striatal dopamine synthesis. During phases of psychotic remission in schizophrenia, dopamine synthesis in the dorsal striatum is reduced. We hypothesized that particularly model-free decision-making is impaired in schizophrenia during psychotic remission and is associated with (i) abnormal dopamine synthesis in dorsal striatum, (ii) aberrant task-activation in dorsal striatum, and (iii) cognitive difficulties in patients (e.g., reduced speed). Methods: 26 patients with chronic schizophrenia, currently in psychotic remission, and 22 healthy controls (matched by age and gender) were enrolled in the study. Model-based/model-free decision-making was evaluated with a twostage Markov decision task, followed by computational modeling of subjects’ learning behavior. Presynaptic dopamine synthesis was assessed by 18F-DOPA positron emission tomography and subsequent graphical Patlak analysis. Taskactivation was measured by functional magnetic resonance imaging. Cognitive impairments were quantified by Trail-Making-Test A  (among others). Associations between decision-making parameters, dopamine synthesis, taskactivation, and cognitive impairments were tested by correlation analyses. Results: Patients with schizophrenia showed selectively impaired model-free decision-making. 18F-DOPA uptake (i.e., presynaptic dopamine synthesis capacity) in the dorsal striatum was decreased in patients. Impaired modelfree decision-making in patients correlated with (i) decreased dopamine synthesis in dorsal striatum, (ii) abnormal task-activation in dorsal striatum, and (iii) lower speed in Trail-Making-Test A. Discussion: Results demonstrate an association of reduced dorsal striatal dopamine synthesis and brain activity with impaired model-free decision-making in schizophrenia, which potentially contributes to cognitive difficulties. [ABSTRACT FROM AUTHOR]

Background: the impact of cognitive impairment on activities of daily living (ADL) is being used as a major criterion for differentiating between mild cognitive impairment (MCI) and dementia. The concept of an ADL threshold that separates MCI from dementia, however, appears to he improbable for several reasons. Objectives: to determine whether complex ADL are impaired in patients with MCI; to examine the usefulness of the assessment of ADL impairment for the diagnosis of MCI; to explore whether both cognitive testing and assessment of impaired ADL are significant predictors of the diagnosis according to the diagnostic gold standard of MCI. Design: cross sectional study. Setting: university-based outpatient clinic. Subjects: a total of 45 elderly MCI patients diagnosed according to research diagnostic criteria and 30 age- matched cognitively unimpaired controls. Methods: clinical assessment Alzheimer's disease Assessment scale, cognitive subscale (ADAS-cog) for the assessment of cognitive functions, Alzheimer's disease Cooperative Study scale for ADL in MCI (ADCS-MCI-ADL) for the assessment of impairments of complex ADL. Statistical evaluation -- Mann--Whitney U tests for significant differences on measures of cognition and everyday functioning. Non-parametric correlations for associations between ADL and cognitive ability. Receiver operator curve (ROC) analyses to identify optimal cut-off scores on the ADCS-MCI-ADL and ADAS-cog scales to differentiate between MCI patients and controls. Binary logistic regression analyses to predict the diagnosis of MCI on the basis of the above-mentioned instruments. Results: patients scored significantly higher than controls on the ADAS cog scale and significantly lower on the ADCS MCI-ADL scale. There was a significant negative correlation of the above-mentioned scales in MCI patients (r = -0.46, P<0.01). Both instruments discriminated well between patients anti controls (ADCS-MCI-ADL: optimal cut- off 52 points, sensitivity 0.89, specificity 0.97; ADAS-cog: optimal cut-off 10 points, sensitivity 0.78, specificity 1.0). With regard to the linear predictor in the logistic regression built, both instruments were strong predictors of the diagnosis according to the diagnostic gold standard (ADCS-MCI-ADL: P = 0.002; ADAS cog: P = 0.041). Conclusion: impairment of ADL is already present in MCI. Therefore, intact ADL cannot be used as a criterion to define the syndrome of MCI and to distinguish it from mild dementia. The assessment of complex ADL is probably useful for the diagnosis of MCI. [ABSTRACT FROM AUTHOR]