Altered Morphological Characteristics Associated With Spatial Working Memory Performance in Children With ADHD.

Direct and indirect effects of fetal irradiation on cortical gray and white matter volume in the macaque

Hallucinations are considered one of the primary symptoms of psychosis; however, their neural basis remains unclear. Voxel-based morphometry (VBM)1 studies have associated hallucinations with gray matter (GM) volume reduction in the superior temporal gyrus in schizophrenia.2 Although hallucinations are associated with brain connectivity,3 few studies have investigated their relationship with white matter (WM) volume. Moreover, these studies have shown inconsistent results.4, 5 The chronicity of illness and long-term medications for schizophrenia may limit the interpretation of previous findings.2 Thus, hallucination studies in clinical high risk for psychosis (CHR) and first-episode psychosis (FEP) are required, with minimal effects of chronicity of illness and medication. However, no VBM study has examined the relationship between hallucinations and WM volume in CHR and FEP. Therefore, we aimed to investigate the regional GM and WM volumes associated with hallucinations in CHR and FEP. We enrolled 57 individuals with CHR, 50 individuals with FEP, and 33 healthy controls (HCs). The Comprehensive Assessment of At-Risk Mental States-Japanese version6 was used to confirm whether ultra-high risk criteria7 were met. Table S1 summarizes the demographic and clinical data of the patients. Hallucination severity was assessed using the Positive and Negative Syndrome Scale (PANSS)8 P3 score. Fig. S1 shows the distribution of the severity of hallucinations. Some of those with a PANSS P3 score of 3 or higher were classified as having CHR because of the low frequency and duration of hallucinations. Magnetic resonance imaging (MRI) data were acquired with a 1.5-T Philips scanner. We examined the association of GM and WM volume with hallucination severity in the group that combined patients with CHR and FEP (CHR/FEP combined group) and performed group comparisons of GM and WM volume between the CHR/FEP combined and HC groups. Age, sex, and intracranial volume were entered as nuisance covariates for each analysis. VBM analysis was conducted using DARTEL9 in SPM12 (https://www.fil.ion.ucl.ac.uk/spm/software/spm12/) with standard smoothing of 8-mm full width at half maximum (FWHM). The initial statistical threshold was set at P < 0.001, uncorrected at the voxel level. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by SPM. Familywise error (FWE) correction at the cluster level (P < 0.05) was applied to identify significant clusters. Appendix S1 provides detailed information on these methods. This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Tohoku University Graduate School of Medicine and Tohoku University Hospital. Written informed consent was obtained from participants aged 18 years or older and from the parents of those under 18 years of age, with written assent from the participants. The anonymity of participants was preserved. WM volume was not significantly correlated with hallucination severity in the CHR/FEP combined group after FWE correction at the cluster level. Reanalysis with 15-mm or 20-mm FWHM filtering did not show significant associations. Additionally, there was no significant difference in the GM and WM volumes between the CHR/FEP combined and HC groups. No regional GM volume abnormalities were significantly correlated with hallucination severity in the CHR/FEP combined group. Appendix S1, Figs. S2–S5, and Tables S2–S5 provide uncorrected results and detailed information regarding these results. To the best of our knowledge, this is the first VBM study to investigate WM volume related to hallucinations in CHR and FEP. We found no significant correlation between WM volume and hallucination severity. In contrast to previous studies in schizophrenia,2, 4, 5 this study examined the brain volume association of hallucinations in CHR and FEP. CHR and FEP are heterogeneous groups in the early stages of mental illness and do not necessarily convert to schizophrenia. Our results indicate that brain disturbances involved in hallucinations in CHR and FEP may be more subtle and/or inconsistent with those in schizophrenia. Diffusion tensor imaging, a neuroimaging method applied to CHR,10 may be suitable for examining structural abnormalities in the development of hallucinations. This study has some limitations. First, information regarding hallucinations is not detailed. Second, the cross-sectional design limited the interpretation of our findings. Third, we used an MRI scanner with a lower field strength than that of recent studies.4 Fourth, there were significant age differences between the groups. Fifth, automatic quality assurance for MRI scans was not performed. In conclusion, advanced neuroimaging studies are needed to reveal the mechanism of hallucinations. This work was supported by JSPS KAKENHI (grant number 18K07586). We thank the participants, staff of the SAFE clinic, and radiological technologists. The authors declare no conflicts of interest. Appendix S1. Supporting information Figure S1. Distribution of hallucination severity. CHR, clinical high risk for psychosis; FEP, first-episode psychosis; PANSS, Positive and Negative Syndrome Scale. Figure S2. Brain regions with lower gray matter volume in the CHR/FEP group compared to the HC group. Statistical threshold was set at P < 0.001, uncorrected at the voxel level. The threshold extent for cluster size was set to k = 117 based on the expected number of voxels per cluster provided by SPM. The full width at half maximum was set to 8-mm. CHR, clinical high risk for psychosis; FEP, first-episode psychosis; HC, healthy controls; SPM, Statistical Parametric Mapping Figure S3. Brain regions with lower white matter volume in the CHR/FEP group compared to the HC group. Statistical threshold was set at P < 0.001, uncorrected at the voxel level. The threshold extent for cluster size was set to k = 129 based on the expected number of voxels per cluster provided by SPM. The full width at half maximum was set to 8-mm. CHR, clinical high risk for psychosis; FEP, first-episode psychosis; HC, healthy controls; SPM, Statistical Parametric Mapping Figure S4. Positive correlation between gray matter volume and hallucination severity in the patients at clinical high risk for psychosis. Statistical threshold was set at P < 0.001, uncorrected at the voxel level. The threshold extent for cluster size was set to k = 101 based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. SPM, Statistical Parametric Mapping Figure S5. Negative correlation between white matter volume and hallucination severity in the patients at clinical high risk for psychosis. Statistical threshold was set at P < 0.001, uncorrected at the voxel level. The threshold extent for cluster size was set to k = 121 based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. SPM, Statistical Parametric Mapping Table S1. Demographic and clinical characteristics of the participants. †Educational level, CP-equivalent dose on MRI scan, PANSS positive, PANSS negative, PANSS general, PANSS total, PANSS P3: hallucinatory behavior, and days from enrollment to MRI scan were analyzed using the t-test. Age and intracranial volume were analyzed using one-way analysis of variance. Sex and antipsychotic use were analyzed using the chi-squared test. Significant results are shown in bold. CHR, clinical high risk for psychosis; CP-equivalent, chlorpromazine equivalent; FEP, first-episode psychosis; HC, healthy controls; PANSS, Positive and Negative Syndrome Scale. Table S2. Between-group comparison of regional gray matter volume. CHR/FEP < HC (extent threshold: 117 voxels). † Uncorrected p-value at voxel level. ‡ familywise error-corrected p-value at the cluster level. k, cluster size at P < 0.001 (uncorrected); CHR, clinical high risk for psychosis; FEP, first-episode psychosis; HC, healthy controls; L/R, left/right hemisphere; MNI, Montreal Neurological Institute. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. Table S3. Between group comparison of regional white matter volume. CHR/FEP < HC (extent threshold: 129 voxels). † Uncorrected P-value at voxel level. ‡ familywise error-corrected p-value at the cluster level. k, cluster size at P < 0.001 (uncorrected); CHR, clinical high risk for psychosis; FEP, first-episode psychosis; HC, healthy controls; L/R, left/right hemisphere; MNI, Montreal Neurological Institute. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. Table S4. Correlation between gray matter volume and hallucination severity in the patients with CHR. Positive correlation (extent threshold: 101 voxels). † Uncorrected p-value at voxel level. ‡ familywise error-corrected p-value at the cluster level. k, cluster size at P < 0.001 (uncorrected); CHR, clinical high risk for psychosis; L/R, left/right hemisphere; MNI, Montreal Neurological Institute. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. Table S5. Correlation between white matter volume and hallucination severity in the patients with CHR. Negative correlation (extent threshold: 121 voxels). † Uncorrected p-value at voxel level. ‡ familywise error-corrected p-value at the cluster level. k, cluster size at P < 0.001 (uncorrected); CHR, clinical high risk for psychosis; L/R, left/right hemisphere; MNI, Montreal Neurological Institute. The extent threshold for cluster size was set based on the expected number of voxels per cluster provided by the SPM. The full width at half maximum was set to 8-mm. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Pathomorphologic brain changes occurring as early as first-episode schizophrenia have been extensively described. Longitudinal studies have demonstrated that these changes may be progressive and associated with clinical outcome. This raises the possibility that antipsychotics might alter such pathomorphologic progression in early-stage schizophrenia. To test a priori hypotheses that olanzapine-treated patients have less change over time in whole brain gray matter volumes and lateral ventricle volumes than haloperidol-treated patients and that gray matter and lateral ventricle volume changes are associated with changes in psychopathology and neurocognition. Longitudinal, randomized, controlled, multisite, double-blind study. Patients treated and followed up for up to 104 weeks. Neurocognitive and magnetic resonance imaging (MRI) assessments performed at weeks 0 (baseline), 12, 24, 52, and 104. Mixed-models analyses with time-dependent covariates evaluated treatment effects on MRI end points and explored relationships between MRI, psychopathologic, and neurocognitive outcomes. Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1). Patients with first-episode psychosis (DSM-IV) and healthy volunteers. Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d). Brain volume changes assessed by MRI. Of 263 randomized patients, 161 had baseline and at least 1 postbaseline MRI evaluation. Haloperidol-treated patients exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not. A matched sample of healthy volunteers (n = 58) examined contemporaneously showed no change in gray matter volume. Patients with first-episode psychosis exhibited a significant between-treatment difference in MRI volume changes. Haloperidol was associated with significant reductions in gray matter volume, whereas olanzapine was not. Post hoc analyses suggested that treatment effects on brain volume and psychopathology of schizophrenia may be associated. The differential treatment effects on brain morphology could be due to haloperidol-associated toxicity or greater therapeutic effects of olanzapine.

Brain-derived Neurotrophic Factor (BDNF) and gray matter volume in bipolar disorder

In cocaine-dependent patients, gray matter (GM) volume reductions have been observed in the frontal lobes that are associated with the duration of cocaine use. Studies are mostly restricted to treatment-seekers and studies in non-treatment-seeking cocaine abusers are sparse. Here, we assessed GM volume differences between 30 non-treatment-seeking cocaine-dependent individuals and 33 non-drug using controls using voxel-based morphometry. Additionally, within the group of non-treatment-seeking cocaine-dependent individuals, we explored the role of frequently co-occurring features such as trait impulsivity (Barratt Impulsivity Scale, BIS), smoking, and depressive symptoms (Beck Depression Inventory), as well as the role of cocaine use duration, on frontal GM volume. Smaller GM volumes in non-treatment-seeking cocaine-dependent individuals were observed in the left middle frontal gyrus. Moreover, within the group of cocaine users, trait impulsivity was associated with reduced GM volume in the right orbitofrontal cortex, the left precentral gyrus, and the right superior frontal gyrus, whereas no effect of smoking severity, depressive symptoms, or duration of cocaine use was observed on regional GM volumes. Our data show an important association between trait impulsivity and frontal GM volumes in cocaine-dependent individuals. In contrast to previous studies with treatment-seeking cocaine-dependent patients, no significant effects of smoking severity, depressive symptoms, or duration of cocaine use on frontal GM volume were observed. Reduced frontal GM volumes in non-treatment-seeking cocaine-dependent subjects are associated with trait impulsivity and are not associated with co-occurring nicotine dependence or depression.

Hemispheric specialization of the lateral prefrontal cortex for strategic processing during spatial and shape working memory

The relationship between adolescent cannabis use and susceptibility to persistent cognitive impairments is poorly understood. We examined the effects of repeated exposure to Δ-9-tetrahydrocannabinol (THC) on reinforcement-related learning and performance of spatial working memory (WM) tasks of varying difficulty in adolescent monkeys. Seven pairs of male adolescent rhesus monkeys, matched for baseline cognitive performance, received vehicle or THC intravenously 5 days/week for 12 months. Performance on 4-item spatial WM trials was assessed throughout the 12-month study period. At the 6-month time point, more difficult novel and distractor 8-item spatial WM trials were added. Residual effects on performance were determined 23 or 71 h after THC or vehicle administration throughout the study. Relative to vehicle-exposed animals, repeated THC exposure was initially associated with significantly slower improvement in performance accuracy on 4-item spatial WM trials; however, this performance difference gradually diminished such that by month 12, accuracy did not significantly differ between vehicle and THC groups. Similarly, for the novel and distractor 8-item trials introduced at month 6, performance accuracy improved more slowly in the THC than in the vehicle group, despite comparable performance between groups on the 4-item task during this same period. These findings suggest that compared to vehicle exposure, THC exposure during adolescence impairs the reinforcement-related learning process required for improved performance on spatial WM tasks, but this impairment might be overcome with continued training, even in the face of ongoing THC exposure.

150. Talairach altas-based volumetric analysis of the brain in schizophrenia

Brain Morphological Changes With Functional Deficit Associated With Sexual Arousal in Postmenopausal Women

Measuring brain morphology with non-invasive structural magnetic resonance imaging is common practice, and can be used to investigate neuroplasticity. Brain morphology changes have been reported over the course of weeks, days, and hours in both animals and humans. If such short-term changes occur even faster, rapid morphological changes while being scanned could have important implications. In a randomized within-subject study on 47 healthy individuals, two high-resolution T1-weighted anatomical images were acquired (á 263 s) per individual. The images were acquired during passive viewing of pictures or a fixation cross. Two common pipelines for analyzing brain images were used: voxel-based morphometry on gray matter (GM) volume and surface-based cortical thickness. We found that the measures of both GM volume and cortical thickness showed increases in the visual cortex while viewing pictures relative to a fixation cross. The increase was distributed across the two hemispheres and significant at a corrected level. Thus, brain morphology enlargements were detected in less than 263 s. Neuroplasticity is a far more dynamic process than previously shown, suggesting that individuals’ current mental state affects indices of brain morphology. This needs to be taken into account in future morphology studies and in everyday clinical practice.

To determine characteristics of brain morphology in children and adolescents with neurofibromatosis type 1 and relate these characteristics to neuropsychological functioning. Neurofibromatosis type 1 is associated with numerous CNS abnormalities and cognitive impairment. Abnormal high signal intensity visible on brain MRI, brain tumors, and macrocephaly are common. Research into links between neuroanatomic and cognitive features has been inconclusive. Fifty-two children and adolescents with neurofibromatosis type 1 were compared with 19 control subjects on several quantitative neuroanatomic and neuropsychological measures. Total brain volume, especially gray matter, was significantly greater for neurofibromatosis type 1 subjects than the control subjects. Group differences in the ratio of gray matter to white matter were more prominent in younger than in older subjects. Volume of gray matter in the subjects with neurofibromatosis type 1 was related to their degree of learning disability. Corpus callosum size was significantly larger for subjects in the neurofibromatosis type 1 group, and diminished performance on measures of academic achievement and visual-spatial and motor skills were associated with greater regional corpus callosum size. Neuroanatomic morphology and the developmental pattern of gray matter and white matter in subjects with neurofibromatosis type 1 differed from in control subjects. Some of these differences are related to the neuropsychological status of the neurofibromatosis type 1 group. We propose that delayed developmental apoptosis results in macrocephaly and a delay in the development of appropriate neuronal connections in children with neurofibromatosis type 1. We further propose that these morphologic delays are related to the cognitive profile of neurofibromatosis type 1.

Previous neuroimaging studies of epilepsy with generalized tonic-clonic seizures (GTCS) focus mainly on adults. However, the neural mechanisms that underline this type of epilepsy remain unclear, especially for children. The aim of the present study was to detect the effect of epilepsy on brains of children with GTCS and to investigate whether the changes in the brain can be used to discriminate between epileptic children and healthy children at the level of the individual. To achieve this purpose, we measured gray matter (GM) volume and fractional amplitude of low-frequency fluctuation (fALFF) differences on multimodel magnetic resonance imaging in 14 children with GTCS and 30 age- and gender-matched healthy controls. The patients showed GM volume reduction and a fALFF increase in the thalamus, hippocampus, temporal and other deep nuclei. A significant decrease of fALFF was mainly found in the default mode network (DMN). In addition, epileptic duration was significantly negatively related to the GM volumes and significantly positively related to the fALFF value of right thalamus. A support vector machine (SVM) applied to the GM volume of the right thalamus correctly identified epileptic children with a statistically significant accuracy of 74.42% (P < 0.002). A SVM applied to the fALFF of the right thalamus correctly identified epileptic children with a statistically significant accuracy of 83.72% (P < 0.002). The consistent neuroimaging results indicated that the right thalamus plays an important role in reflecting the chronic damaging effect of GTCS epilepsy in children. The length of time of a child's epileptic history was correlated with greater GM volume reduction and a fALFF increase in the right thalamus. GM volumes and fALFF values in the right thalamus can identify children with GTCS from the healthy controls with high accuracy and at an individual subject level. These results are likely to be valuable in explaining the clinical problems and understanding the brain abnormalities underlying this disorder.

Larger gray matter (GM) volume in healthy children is correlated with higher IQ. Children with neurofibromatosis type 1 (NF1) have larger brains, their magnetic resonance images frequently show T2-weighted hyperintensities, and their IQs are lower. To confirm the hypotheses that (1) children with NF1 have larger GM and white matter volumes, (2) the greatest volume differences are in the frontal and parietal regions and in children with NF1 with hyperintensities, and (3) GM volume is inversely related to IQ in children with NF1. Wechsler Intelligence Scale for Children-Third Edition IQ testing and measurement of cerebral volumes and hyperintensities in brain magnetic resonance images were performed on 36 children with NF1 and on 36 matched relatives who served as control subjects. Gray matter and white matter volumes were significantly larger in children with NF1. The greatest difference was observed in cerebral white matter volume, predominantly in the frontal lobes, whereas the greatest difference in GM volume was in the temporal, parietal, and occipital regions. In controls, IQ was significantly related to GM volume, but in children with NF1, IQ was not inversely associated with GM volume, although IQs of children with NF1 were significantly lower. Children with NF1 do not have the normal relationship between GM volume and IQ. Larger GM volume in the posterior brain regions and larger white matter volumes in the frontal brain regions contribute to the larger brain volume in children with NF1.

Inactivation of the nucleus reuniens/rhomboid causes a delay-dependent impairment of spatial working memory

The FKBP5 gene codes for a co-chaperone that regulates glucocorticoid receptor sensitivity and thereby impacts the reactivity of the hypothalamic-pituitary-adrenal (HPA)-axis. Evidence suggested that subjects exposed to childhood abuse and carrying the TT genotype of the FKBP5 gene single nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to stress-related disorders. The hypothesis that abused TT genotype carriers show changes in gray matter (GM) volumes in affect-processing brain areas was investigated. About 1,826 Caucasian subjects (age ≤ 65 years) from the general population [Study of Health in Pomerania (SHIP)] in Germany were investigated. The interaction between rs1360780 and child abuse (Childhood Trauma Questionnaire) and its effect on GM were analyzed. Voxel-based whole-brain interaction analysis revealed three large clusters (FWE-corrected) of reduced GM volumes comprising the bilateral insula, the superior and middle temporal gyrus, the bilateral hippocampus, the right amygdala, and the bilateral anterior cingulate cortex in abused TT carriers. These results were not confounded by major depressive disorders. In region of interest analyses, highly significant volume reductions in the right hippocampus/parahippocampus, the bilateral anterior and middle cingulate cortex, the insula, and the amygdala were confirmed in abused TT carriers compared with abused CT/CC carriers. The results supported the hypothesis that the FKBP5 rs1360780 TT genotype predisposes subjects who have experienced childhood abuse to widespread structural brain changes in the subcortical and cortical emotion-processing brain areas. Those brain changes might contribute to an increased vulnerability of stress-related disorders in TT genotype carriers.