T. Van Amelsvoort

Explicit and Implicit Neural Mechanisms for Processing of Social Information From Facial Expressions: A Functional Magnetic Resonance Imaging Study

The processing of changing nonverbal social signals such as facial expressions is poorly understood, and it is unknown if different pathways are activated during effortful (explicit), compared to implicit, processing of facial expressions. Thus we used fMRI to determine which brain areas subserve processing of high‐valence expressions and if distinct brain areas are activated when facial expressions are processed explicitly or implicitly. Nine healthy volunteers were scanned (1.5T GE Signa with ANMR, TE/TR 40/3,000 ms) during two similar experiments in which blocks of mixed happy and angry facial expressions (“on” condition) were alternated with blocks of neutral faces (control “off” condition). Experiment 1 examined explicit processing of expressions by requiring subjects to attend to, and judge, facial expression. Experiment 2 examined implicit processing of expressions by requiring subjects to attend to, and judge, facial gender, which was counterbalanced in both experimental conditions. Processing of facial expressions significantly increased regional blood oxygenation level‐dependent (BOLD) activity in fusiform and middle temporal gyri, hippocampus, amygdalohippocampal junction, and pulvinar nucleus. Explicit processing evoked significantly more activity in temporal lobe cortex than implicit processing, whereas implicit processing evoked significantly greater activity in amygdala region. Mixed high‐valence facial expressions are processed within temporal lobe visual cortex, thalamus, and amygdalohippocampal complex. Also, neural substrates for explicit and implicit processing of facial expressions are dissociable: explicit processing activates temporal lobe cortex, whereas implicit processing activates amygdala region. Our findings confirm a neuroanatomical dissociation between conscious and unconscious processing of emotional information. Hum. Brain Mapping 9:93–105, 2000.

An investigation of the neuropsychological profile in adults with velo-cardio-facial syndrome (VCFS)

Velo-cardio-facial syndrome (VCFS) is associated with deletions on the long arm of chromosome 22, mild intellectual disability, poor social interaction and a high prevalence of psychosis. However, to date there have been no studies investigating the neuropsychological functioning of adults with VCFS. We compared 19 adults with VCFS with 19 age, gender and IQ matched controls using a comprehensive neuropsychological battery. Compared to controls, adults with VCFS had significant impairments in visuoperceptual ability (Visual Object and Space Perception Battery), problem solving and planning (Tower of London) and abstract and social thinking (Comprehension WAIS-R). It is likely that haploinsufficiency (reduced gene dosage) of a neurodevelopmental gene or genes mapping to chromosome 22q11 underlies the cognitive deficits observed in individuals with VCFS.

Neurocognitive functioning before and after the first psychotic episode: does psychosis result in cognitive deterioration?

BACKGROUND Cognitive impairment is considered to be a core characteristic of schizophrenia. The relationship between psychosis and cognitive deterioration, however, remains unclear. This longitudinal study investigated the neuropsychological functioning of patients before and after their first psychotic episode. Cognitive functioning of participants who later developed a psychosis was compared to that of people at ultra-high risk (UHR) for psychosis who did not develop psychosis at follow-up and healthy controls.MethodParticipants were 41 persons at UHR for psychosis (the UHR group), of whom 17 developed psychosis between the first and second assessment. Seventeen healthy controls were included in the study. Cognitive performance was assessed at intake (T0) and again after 18 months (T1). The areas of cognitive functioning assessed include verbal memory and learning, visuospatial working memory, executive function, sustained attention and motor speed. RESULTS The transition group did not perform significantly worse at the second assessment than at the first on any of the outcome measures. The UHR group performed better on a verbal learning and memory test at T1 compared to T0. At T0, the control group scored significantly better than the UHR group and the transition group on the verbal learning and memory test and the verbal fluency test. CONCLUSIONS The results indicate that no cognitive deterioration occurs during the first psychotic episode. Problems in verbal memory may be present before the first episode of psychosis.

Effects of estrogen replacement therapy on human brain aging: An in vivo 1H MRS study

Estrogen replacement therapy (ERT) may preserve cognitive function in postmenopausal women, but the mechanism is unknown. Thus, the authors studied aging of parietal lobe and hippocampus using proton MR spectroscopy. ERT naïve postmenopausal women had a significant increase in choline-containing compounds (Cho) compared to long-term ERT users and young women. Cho reflects increased neuronal/glial membrane turnover. Thus, ERT’s “neuroprotective” effect may include modulating the effects of age on neural integrity in brain regions involved in cognitive function.

Genetic variation in COMT and PRODH is associated with brain anatomy in patients with schizophrenia

Haploinsufficiency of 22q11 genes including catechol‐O‐methyltransferase (COMT) and proline dehydrogenase (PRODH) may result in structural and functional brain abnormalities and increased vulnerability to schizophrenia as observed in patients with microdeletions of 22q11. Thus, COMT and PRODH could be modifier genes for schizophrenia. We examined association of polymorphisms in COMT and PRODH with brain anatomy in young patients with schizophrenia and schizoaffective disorder. We acquired structural magnetic resonance imaging data from 51 male patients and genotyped two single nucleotide polymorphisms (SNPs) in the COMT gene and three in the PRODH gene. Statistical Parametric Mapping software and optimized voxel‐based morphometry were used to determine regional gray matter (GM) and white matter (WM) density differences, and total GM and WM volume differences between genotype groups. Two nonsynonymous SNPs in the PRODH gene were associated with bilateral frontal WM density reductions and an SNP in the P2 promoter region of COMT (rs2097603) was associated with GM increase in the right superior temporal gyrus. Furthermore, we found evidence for COMT and PRODH epistasis: in patients with a COMT Val allele (rs4680) and with one or two mutated PRODH alleles, we observed increased WM density in the left inferior frontal lobe. Our results suggest that genetic variation in COMT and PRODH has significant effects on brain regions known to be affected in schizophrenia. Further research is needed to investigate the role of 22q11 genes on brain structure and function and their role in vulnerability for schizophrenia.

Effects of a functional COMT polymorphism on brain anatomy and cognitive function in adults with velo-cardio-facial syndrome.

BACKGROUND Velo-cardio-facial syndrome (VCFS) is associated with deletions at chromosome 22q11, abnormalities in brain anatomy and function, and schizophrenia-like psychosis. Thus it is assumed that one or more genes within the deleted region are crucial to brain development. However, relatively little is known about how genetic variation at 22q11 affects brain structure and function. One gene on 22q11 is catechol-O-methyltransferase (COMT): an enzyme that degrades dopamine and contains a functional polymorphism (Val158Met) affecting enzyme activity. Here, we investigated the effect of COMT Val158Met polymorphism on brain anatomy and cognition in adults with VCFS. METHOD The COMT Val158Met polymorphism was genotyped for 26 adults with VCFS on whom DNA was available. We explored its effects on regional brain volumes using hand tracing approaches; on regional grey- and white-matter density using computerized voxel-based analyses; and measures of attention, IQ, memory, executive and visuospatial function using a comprehensive neuropsychological test battery. RESULTS After corrections for multiple comparisons Val-hemizygous subjects, compared with Met-hemizygotes, had a significantly larger volume of frontal lobes. Also, Val-hemizygotes had significantly increased grey matter density in cerebellum, brainstem, and parahippocampal gyrus, and decreased white matter density in the cerebellum. No significant effects of COMT genotype on neurocognitive performance were found. CONCLUSIONS COMT genotype effects on brain anatomy in VCFS are not limited to frontal regions but also involve other structures previously implicated in VCFS. This suggests variation in COMT activity is implicated in brain development in VCFS.

Reduced striatal D2 receptor binding in myoclonus-dystonia

PurposeTo study striatal dopamine D2 receptor availability in DYT11 mutation carriers of the autosomal dominantly inherited disorder myoclonus–dystonia (M–D).MethodsFifteen DYT11 mutation carriers (11 clinically affected) and 15 age- and sex-matched controls were studied using 123I-IBZM SPECT. Specific striatal binding ratios were calculated using standard templates for striatum and occipital areas.ResultsMultivariate analysis with corrections for ageing and smoking showed significantly lower specific striatal to occipital IBZM uptake ratios (SORs) both in the left and right striatum in clinically affected patients and also in all DYT11 mutation carriers compared to control subjects.ConclusionsOur findings are consistent with the theory of reduced dopamine D2 receptor (D2R) availability in dystonia, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out.

Improvement of subjective well-being and enduring symptomatic remission, a 5-year follow-up of first episode schizophrenia.

INTRODUCTION The aim of this prospective study was to compare the predictive validity of early improvement of subjective experience and early improvement of rater assessed symptoms on enduring symptomatic remission (ESR) status during 5 years follow. METHODS 110 consecutively admitted patients suffering from a first episode of schizophrenia or related disorders were investigated. We defined early improvement of subjective well-being as a delta-score of the total Subjective Well-being under Neuroleptics scale-20 item version (SWN-K) at admission and after 6 weeks treatment. The severity of psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) at admission, 6 weeks, 6 months, 3 and 5 years after admission. Enduring symptomatic remission (ESR) was defined as complying to the symptomatic remission criteria at PANSS assessment at 6 months and 5 years and continuing this state between 6 months and 5 years follow-up. Paired-samples and independent t-test were used to compare means. RESULTS Patients with ESR (n=30) had a higher mean improvement of subjective well-being during early treatment as assessed with the SWN-K than those without ESR (n=74) (p=0.004). Early symptomatic improvement as assessed with the PANSS was not related to ESR (p=0.95). DISCUSSION Early improvement of subjective well-being is related to ESR in first episode schizophrenia or related disorders.

Preliminary evidence for reduced frontal white matter integrity in subjects at ultra-high-risk for psychosis

In subjects with a genetic high-risk of psychosis, diffusion tensor imaging (DTI) has shown decreased white matter anisotropy in the cingulate and angular gyri bilaterally (Hoptman et al., 2008) and in the anterior limb of the internal capsules (Muñoz Maniega et al., 2008). In this study we examined white matter integrity in subjects at ultra-highrisk (UHR) for psychosis with DTI, in comparisonwith recentonset schizophrenia patients. Ten male subjects at UHR for psychosis (mean age 21.6 years, standard deviation (SD)=2.8) were included after assessment with the Structured Interview for Prodromal Syndromes (SIPS; Miller et al., 2002) and according to internationally defined criteria (Klosterkötter et al., 2005): attenuated psychotic symptoms (e.g. odd beliefs, paranoid ideation) or brief limited psychosis with spontaneous remission in less than 1week; or a decline in functioning in the past year (30% reduction in Global Assessment of Functioning scale) plus a genetic risk (schizotypal personality disorder); or two 2 “basic symptoms” (cognitive, perceptual, emotional and social disturbances). UHR subjects did not use any medication at time of MRI (three subjects used antipsychotic medication in the past). Eight male patients with a recentonset of schizophrenia and two male patients with schizoaffective disorder (21.2 years, SD=3.0) were recruited from the Adolescent Clinic, Amsterdam. All recent-onset patients used antipsychotic medication. Ten male healthy controls (21.1 years, SD=2.8) were included. All participants were matched for handedness and level of education and gave written informed consent as approved by the local and national medical ethics committees. MR images were acquired with a 3 Tesla Philips scanner. For DTI spin-echo single shot EPI was used, with: TR 48316248 ms/TE 94 ms; b=0 and b=1000 s/mm; 16 noncolinear directions, each direction scanned twice; 48 continuous slices, voxel size 3×3.5×2.2 mm, FOV 230–256 mm, image matrix 256×256. All data were processed with Statistical Parametric Mapping Software SPM2 using optimized voxel basedmorphometry. T1-weighted images were normalized to standard space (Montreal Neurological Institute, MNI). Prior images of white matter (WM) were generated based on the existing (MNI) T1 weighted template in SPM2, and were used

Effect of long-term estrogen therapy on dopaminergic responsivity in post-menopausal women--a preliminary study.

Females have a higher prevalence than men of neuropsychiatric disorders in which dopaminergic abnormalities play a prominent role, e.g. very late-onset schizophrenia and Parkinsons disease (PD). The biological basis of these sex differences is unknown but may include modulation of the dopaminergic system by sex hormones, as there is preliminary evidence that estrogen modulates treatment response in these disorders. Furthermore, sex differences in dopamine-mediated cognitive decline suggest estrogen may also play a role in healthy aging. However, the effects of estrogen on the dopaminergic system are poorly understood, and nobody has examined the effect of long-term estrogen therapy (ET) on this system. We compared dopaminergic responsivity (growth hormone (GH) response to apomorphine) in post-menopausal women on ET to women who were ET-naïve. GH response to subcutaneous apomorphine (0.005 mg/kg) was measured in two groups of healthy post-menopausal women aged between 55 and 70 years: those taking ET (n = 13) and those who had never taken ET (n = 13). Neither group was taking any other medication. GH was measured at 15 min intervals from -30 min before administration of apomorphine to 90 min post-administration. GH response was measured in two ways: area under the curve (AUC) and maximum response over baseline (GH). There were no between-group differences in demographic or baseline variables. The ET treated women had a significantly greater (p = 0.03) AUC than ET naïve women (mean +/- S.D.; 5.3 +/- 4.7 vs. 2.6 +/- 2.3). However, (GH) did not differ significantly between groups (6.1 mU/l +/- 6.2 vs. 2.7 mU/l +/- S.D. = 4.1). Also, analysis of GH response over time revealed a significant main effect of time (p < 0.0005), and a group by time interaction (p = 0.004) , but no significant main effect of group. Our results suggest that ET may enhance dopaminergic responsivity in post-menopausal women. Estrogen deficiency following menopause may partly explain age and gender differences in late-onset neuropsychiatric disorders.