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1.  Legal responses to neuroscience 
doi:10.1503/jpn.160147
PMCID: PMC5082506  PMID: 27768561
2.  Dysfunctional insular connectivity during reward prediction in patients with first-episode psychosis 
Background
Increasing evidence indicates that psychosis is associated with abnormal reward processing. Imaging studies in patients with first-episode psychosis (FEP) have revealed reduced activity in diverse brain regions, including the ventral striatum, insula and anterior cingulate cortex (ACC), during reward prediction. However, whether these reductions in local brain activity are due to altered connectivity has rarely been explored.
Methods
We applied dynamic causal modelling and Bayesian model selection to fMRI data during the Salience Attribution Task to investigate whether patients with FEP showed abnormal modulation of connectivity between the ventral striatum, insula and ACC induced by rewarding cues and whether these changes were related to positive psychotic symptoms and atypical antipsychotic medication.
Results
The model including reward-induced modulation of insula–ACC connectivity was the best fitting model in each group. Compared with healthy controls (n = 19), patients with FEP (n = 29) revealed reduced right insula–ACC connectivity. After subdividing patients according to current antipsychotic medication, we found that the reduced insula–ACC connectivity relative to healthy controls was observed only in untreated patients (n = 17), not in patients treated with antipsychotics (n = 12), and that it correlated negatively with unusual thought content in untreated patients with FEP.
Limitations
The modest sample size of untreated patients with FEP was a limitation of our study.
Conclusion
This study indicates that insula–ACC connectivity during reward prediction is reduced in untreated patients with FEP and related to the formation of positive psychotic symptoms. Our study further suggests that atypical antipsychotics may reverse connectivity between the insula and the ACC during reward prediction.
doi:10.1503/jpn.150234
PMCID: PMC5082507  PMID: 26854756
3.  Partially restored resting-state functional connectivity in women recovered from anorexia nervosa 
Background
We have previously shown increased resting-state functional connectivity (rsFC) in the frontoparietal network (FPN) and the default mode network (DMN) in patients with acute anorexia nervosa. Based on these findings we investigated within-network rsFC in patients recovered from anorexia nervosa to examine whether these abnormalities are a state or trait marker of the disease. To extend the understanding of functional connectivity in patients with anorexia nervosa, we also estimated rsFC between large-scale networks.
Methods
Girls and women recovered from anorexia nervosa and pair-wise, age- and sex-matched healthy controls underwent a resting-state fMRI scan. Using independent component analyses (ICA), we isolated the FPN, DMN and salience network. We used standard comparisons as well as a hypothesis-based approach to test the findings of our previous rsFC study in this recovered cohort. Temporal correlations between network time-course pairs were computed to investigate functional network connectivity (FNC).
Results
Thirty-one patients recovered from anorexia nervosa and 31 controls participated in our study. Standard group comparisons revealed reduced rsFC between the dorsolateral prefrontal cortex (dlPFC) and the FPN in the recovered group. Using a hypothesis-based approach we extended the previous finding of increased rsFC between the angular gyrus and the FPN in patients recovered from anorexia nervosa. No group differences in FNC were revealed.
Limitations
The study design did not allow us to conclude that the difference found in rsFC constitutes a scar effect of the disease.
Conclusion
This study suggests that some abnormal rsFC patterns found in patients recovered from anorexia nervosa normalize after long-term weight restoration, while distorted rsFC in the FPN, a network that has been associated with cognitive control, may constitute a trait marker of the disorder.
doi:10.1503/jpn.150259
PMCID: PMC5082508  PMID: 27045551
4.  Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals 
Background
Neuroinflammatory processes are increasingly believed to participate in the pathophysiology of a number of major psychiatric diseases, including depression. Immune activation stimulates the conversion of the amino acid tryptophan to kynurenine, leading to the formation of neuroactive metabolites, such as quinolinic acid and kynurenic acid. These compounds affect glutamatergic neurotransmission, which plays a prominent role in depressive pathology. Increased tryptophan degradation along the kynurenine pathway (KP) has been proposed to contribute to disease etiology.
Methods
We used postmortem brain tissue from the ventrolateral prefrontal cortex (VLPFC) to assess tissue levels of tryptophan and KP metabolites, the expression of several KP enzymes and a series of cytokines as well as tissue pathology, including microglial activation. Tissue samples came from nonpsychiatric controls (n = 36) and individuals with depressive disorder not otherwise specified (DD-NOS, n = 45) who died of natural causes, homicide, accident, or suicide.
Results
We found a reduction in the enzymatic conversion of tryptophan to kynurenine, determined using the kynurenine:tryptophan ratio, and reduced messenger RNA expression of the enzymes indoleamine-2,3-dioxygenase 1 and 2 and tryptophan-2,3-dioxygenase in depressed individuals irrespective of the cause of death. These findings correlated with reductions in the expression of several cytokines, including interferon-γ and tumour necrosis factor-α. Notably, quinolinic acid levels were also lower in depressed individuals than controls.
Limitations
Information on the use of antidepressants and other psychotropic medications was insufficient for statistical comparisons.
Conclusion
Contrary to expectations, the present results indicate that depression, in the absence of medical illness or an overt inflammatory process, is associated with compromised, rather than increased, KP metabolism in the VLPFC.
doi:10.1503/jpn.150226
PMCID: PMC5082509  PMID: 27070351
5.  Male-typical visuospatial functioning in gynephilic girls with gender dysphoria — organizational and activational effects of testosterone 
Background
Sex differences in performance and regional brain activity during mental rotation have been reported repeatedly and reflect organizational and activational effects of sex hormones. We investigated whether adolescent girls with gender dysphoria (GD), before and after 10 months of testosterone treatment, showed male-typical brain activity during a mental rotation task (MRT).
Methods
Girls with GD underwent fMRI while performing the MRT twice: when receiving medication to suppress their endogenous sex hormones before onset of testosterone treatment, and 10 months later during testosterone treatment. Two age-matched control groups participated twice as well.
Results
We included 21 girls with GD, 20 male controls and 21 female controls in our study. In the absence of any group differences in performance, control girls showed significantly increased activation in frontal brain areas compared with control boys (pFWE = 0.012). Girls with GD before testosterone treatment differed significantly in frontal brain activation from the control girls (pFWE = 0.034), suggesting a masculinization of brain structures associated with visuospatial cognitive functions. After 10 months of testosterone treatment, girls with GD, similar to the control boys, showed increases in brain activation in areas implicated in mental rotation.
Limitations
Since all girls with GD identified as gynephilic, their resemblance in spatial cognition with the control boys, who were also gynephilic, may have been related to their shared sexual orientation rather than their shared gender identity. We did not account for menstrual cycle phase or contraceptive use in our analyses.
Conclusion
Our findings suggest atypical sexual differentiation of the brain in natal girls with GD and provide new evidence for organizational and activational effects of testosterone on visuospatial cognitive functioning.
doi:10.1503/jpn.150147
PMCID: PMC5082510  PMID: 27070350
6.  COMT and DAT1 genes are associated with hyperactivity and inattention traits in the 1993 Pelotas Birth Cohort: evidence of sex-specific combined effect 
Background
Attention-deficit/hyperactivity disorder (ADHD) symptoms are dimensionally distributed in the population. This study aimed to assess the role of the catechol-O-methyltransferase (COMT) and of the dopamine transporter (DAT1) genes on ADHD symptoms in the general population.
Methods
We investigated 4101 individuals from the 1993 Pelotas Birth Cohort Study using the parent version of the Strengths and Difficulties Questionnaire (SDQ) at ages 11 and 15 years. The SDQ hyperactivity/inattention scores were the main outcomes.
Results
Linear regression analyses demonstrated that the increasing number of COMT158Val and DAT1 10R alleles significantly predicted increasing SDQ hyperactivity/inattention scores in boys at both 11 and 15 years of age (β coefficient = 0.049, t = 2.189, p = 0.029, R2 = 0.012, and β coefficient = 0.064, t = 2.832, p = 0.005, R2 = 0.008, respectively). The presence of both COMT158Val and DAT1 10R alleles was also associated with full categorical ADHD diagnosis at 18 years of age in boys (χ2 = 4.561, p = 0.033, odds ratio 2.473, 95% confidence interval 1.048–5.838) from this cohort. We did not observe these associations in girls.
Limitations
Our analyses of SDQ hyperactivity/inattention scores were not corrected for SDQ scores of conduct problems because these variables were highly correlated.
Conclusion
This study demonstrates a role for COMT and DAT1 genes on hyperactivity/inattention symptoms and provides further support for ADHD as the extreme of traits that vary in the population. It also confirms previous evidence for sexual dimorphism on COMT and DAT1 gene expression.
doi:10.1503/jpn.150270
PMCID: PMC5082511  PMID: 27327562
7.  Common susceptibility variants are shared between schizophrenia and psoriasis in the Han Chinese population 
Background
Previous studies have shown that individuals with schizophrenia have a greater risk for psoriasis than a typical person. This suggests that there might be a shared genetic etiology between the 2 conditions. We aimed to characterize the potential shared genetic susceptibility between schizophrenia and psoriasis using genome-wide marker genotype data.
Methods
We obtained genetic data on individuals with psoriasis, schizophrenia and control individuals. We applied a marker-based coheritability estimation procedure, polygenic score analysis, a gene set enrichment test and a least absolute shrinkage and selection operator regression model to estimate the potential shared genetic etiology between the 2 diseases. We validated the results in independent schizophrenia and psoriasis cohorts from Singapore.
Results
We included 1139 individuals with psoriasis, 744 with schizophrenia and 1678 controls in our analysis, and we validated the results in independent cohorts, including 441 individuals with psoriasis (and 2420 controls) and 1630 with schizophrenia (and 1860 controls). We estimated that a large fraction of schizophrenia and psoriasis risk could be attributed to common variants (h2SNP = 29% ± 5.0%, p = 2.00 × 10−8), with a coheritability estimate between the traits of 21%. We identified 5 variants within the human leukocyte antigen (HLA) gene region, which were most likely to be associated with both diseases and collectively conferred a significant risk effect (odds ratio of highest risk quartile = 6.03, p < 2.00 × 10−16). We discovered that variants contributing most to the shared heritable component between psoriasis and schizophrenia were enriched in antigen processing and cell endoplasmic reticulum.
Limitations
Our sample size was relatively small. The findings of 5 HLA gene variants were complicated by the complex structure in the HLA region.
Conclusion
We found evidence for a shared genetic etiology between schizophrenia and psoriasis. The mechanism for this shared genetic basis likely involves immune and calcium signalling pathways.
doi:10.1503/jpn.150210
PMCID: PMC5082512  PMID: 27091718
8.  The effect of methylphenidate intake on brain structure in adults with ADHD in a placebo-controlled randomized trial 
Background
Based on animal research several authors have warned that the application of methylphenidate, the first-line drug for the treatment of attention-deficit/hyperactivity disorder (ADHD), might have neurotoxic effects potentially harming the brain. We investigated whether methylphenidate application, over a 1-year period, results in cerebral volume decrease.
Methods
We acquired structural MRIs in a double-blind study comparing methylphenidate to placebo. Global and regional brain volumes were analyzed at baseline, after 3 months and after 12 months using diffeomorphic anatomic registration through exponentiated lie algebra.
Results
We included 131 adult patients with ADHD into the baseline sample, 98 into the 3-month sample (54 in the methylphenidate cohort and 44 in the placebo cohort) and 76 into the 1-year sample (37 in the methylphenidate cohort and 29 in the placebo cohort). Methylphenidate intake compared with placebo did not lead to any detectable cerebral volume loss; there was a trend toward bilateral cerebellar grey matter increase.
Limitations
Detecting possible neurotoxic effects of methylphenidate might require a longer observation period.
Conclusion
There is no evidence of grey matter volume loss after 1 year of methylphenidate treatment in adult patients with ADHD.
doi:10.1503/jpn.150320
PMCID: PMC5082513  PMID: 27575717
9.  Clozapine for the management of persistent catatonia 
doi:10.1503/jpn.150352
PMCID: PMC5082514  PMID: 27768562
10.  Concepts and misconceptions regarding clinical staging models 
doi:10.1503/jpn.160196
PMCID: PMC5082515  PMID: 27768563
12.  Objective sleep disturbances are associated with greater waking resting-state connectivity between the retrosplenial cortex/hippocampus and various nodes of the default mode network 
Background
Psychological models highlight the bidirectional role of self-referential processing, introspection, worry and rumination in the development and maintenance of insomnia; however, little is known about the underlying neural substrates. Default mode network (DMN) functional connectivity has been previously linked to these cognitive processes.
Methods
We used fMRI to investigate waking DMN functional connectivity in a well-characterized sample of patients with primary insomnia (PI) and good sleeper controls.
Results
We included 20 patients with PI (8 men and 12 women, mean age 42.7 ± 13.4 yr) and 20 controls (8 men and 12 women, mean age 44.1 ± 10.6 yr) in our study. While no between-group differences in waking DMN connectivity were observed, exploratory analyses across all participants suggested that greater waking connectivity between the retrosplenial cortex/hippocampus and various nodes of the DMN was associated with lower sleep efficiency, lower amounts of rapid eye movement sleep and greater sleep-onset latency.
Limitations
Owing to the cross-sectional nature of the study, conclusions about causality cannot be drawn.
Conclusion
As sleep disturbances represent a transdiagnostic symptom that is characteristic of nearly all psychiatric disorders, our results may hold particular relevance to previous findings of increased DMN connectivity levels in patients with psychiatric disorders.
doi:10.1503/jpn.140290
PMCID: PMC5008918  PMID: 26809225
13.  Prediction error and somatosensory insula activation in women recovered from anorexia nervosa 
Background
Previous research in patients with anorexia nervosa showed heightened brain response during a taste reward conditioning task and heightened sensitivity to rewarding and punishing stimuli. Here we tested the hypothesis that individuals recovered from anorexia nervosa would also experience greater brain activation during this task as well as higher sensitivity to salient stimuli than controls.
Methods
Women recovered from restricting-type anorexia nervosa and healthy control women underwent fMRI during application of a prediction error taste reward learning paradigm.
Results
Twenty-four women recovered from anorexia nervosa (mean age 30.3 ± 8.1 yr) and 24 control women (mean age 27.4 ± 6.3 yr) took part in this study. The recovered anorexia nervosa group showed greater left posterior insula activation for the prediction error model analysis than the control group (family-wise error– and small volume–corrected p < 0.05). A group × condition analysis found greater posterior insula response in women recovered from anorexia nervosa than controls for unexpected stimulus omission, but not for unexpected receipt. Sensitivity to punishment was elevated in women recovered from anorexia nervosa.
Limitations
This was a cross-sectional study, and the sample size was modest.
Conclusion
Anorexia nervosa after recovery is associated with heightened prediction error–related brain response in the posterior insula as well as greater response to unexpected reward stimulus omission. This finding, together with behaviourally increased sensitivity to punishment, could indicate that individuals recovered from anorexia nervosa are particularly responsive to punishment. The posterior insula processes somatosensory stimuli, including unexpected bodily states, and greater response could indicate altered perception or integration of unexpected or maybe unwanted bodily feelings. Whether those findings develop during the ill state or whether they are biological traits requires further study.
doi:10.1503/jpn.150103
PMCID: PMC5008919  PMID: 26836623
14.  Proactive response inhibition abnormalities in the sensorimotor cortex of patients with schizophrenia 
Background
Previous studies of response inhibition in patients with schizophrenia have focused on reactive inhibition tasks (e.g., stop-signal, go/no-go), primarily observing lateral prefrontal cortex abnormalities. However, recent studies suggest that purposeful and sustained (i.e., proactive) inhibition may also be affected in these patients.
Methods
Patients with chronic schizophrenia and healthy controls underwent fMRI while inhibiting motor responses during multisensory (audiovisual) stimulation. Resting state data were also collected.
Results
We included 37 patients with schizophrenia and 37 healthy controls in our study. Both controls and patients with schizophrenia successfully inhibited the majority of overt motor responses. Functional results indicated basic inhibitory failure in the lateral premotor and sensorimotor cortex, with opposing patterns of positive (schizophrenia) versus negative (control) activation. Abnormal activity was associated with independently assessed signs of psychomotor retardation. Patients with schizophrenia also exhibited unique activation of the pre–supplementary motor area (pre-SMA)/SMA and precuneus relative to baseline as well as a failure to deactivate anterior nodes of the default mode network. Independent resting-state connectivity analysis indicated reduced connectivity between anterior (task results) and posterior regions of the sensorimotor cortex for patients as well as abnormal connectivity between other regions (cerebellum, thalamus, posterior cingulate gyrus and visual cortex).
Limitations
Aside from rates of false-positive responses, true proactive response inhibition tasks do not provide behavioural metrics that can be independently used to quantify task performance.
Conclusion
Our results suggest that basic cortico-cortico and intracortical connections between the sensorimotor cortex and adjoining regions are impaired in patients with schizophrenia and that these impaired connections contribute to inhibitory failures (i.e., a positive rather than negative hemodynamic response).
doi:10.1503/jpn.150097
PMCID: PMC5008920  PMID: 26883319
15.  Cocaine cue–induced dopamine release in the human prefrontal cortex 
Background
Accumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers. Whether these same cues provoke DA release in the human prefrontal cortex remains unknown.
Methods
We used high-resolution positron emission tomography with [18F]fallypride to measure cortical and striatal DA D2/3 receptor availability in the presence versus absence of drug-related cues in volunteers with current cocaine dependence.
Results
Twelve individuals participated in our study. Among participants reporting a craving response (9 of 12), exposure to the cocaine cues significantly decreased [18F]fallypride binding potential (BPND) values in the medial orbitofrontal cortex and striatum. In all 12 participants, individual differences in the magnitude of craving correlated with BPND changes in the medial orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate, and striatum. Consistent with the presence of autoreceptors on mesostriatal but not mesocortical DA cell bodies, midbrain BPND values were significantly correlated with changes in BPND within the striatum but not the cortex. The lower the midbrain D2 receptor levels, the greater the striatal change in BPND and self-reported craving.
Limitations
Limitations of this study include its modest sample size, with only 2 female participants. Newer tracers might have greater sensitivity to cortical DA release.
Conclusion
In people with cocaine use disorders, the presentation of drug-related cues induces DA release within cortical and striatal regions. Both effects are associated with craving, but only the latter is regulated by midbrain autoreceptors. Together, the results suggest that cortical and subcortical DA responses might both influence drug-focused incentive motivational states, but with separate regulatory mechanisms.
doi:10.1503/jpn.150207
PMCID: PMC5008921  PMID: 26900792
16.  Global brain connectivity alterations in patients with schizophrenia and bipolar spectrum disorders 
Background
The human brain is organized into functionally distinct modules of which interactions constitute the human functional connectome. Accumulating evidence has implicated perturbations in the patterns of brain connectivity across a range of neurologic and neuropsychiatric disorders, but little is known about diagnostic specificity. Schizophrenia and bipolar disorders are severe mental disorders with partly overlapping symptomatology. Neuroimaging has demonstrated brain network disintegration in the pathophysiologies; however, to which degree the 2 diagnoses present with overlapping abnormalities remains unclear.
Methods
We collected resting-state fMRI data from patients with schizophrenia or bipolar disorder and from healthy controls. Aiming to characterize connectivity differences across 2 severe mental disorders, we derived global functional connectivity using eigenvector centrality mapping, which allows for regional inference of centrality or importance in the brain network.
Results
Seventy-one patients with schizophrenia, 43 with bipolar disorder and 196 healthy controls participated in our study. We found significant effects of diagnosis in 12 clusters, where pairwise comparisons showed decreased global connectivity in high-centrality clusters: sensory regions in patients with schizophrenia and subcortical regions in both patient groups. Increased connectivity occurred in frontal and parietal clusters in patients with schizophrenia, with intermediate effects in those with bipolar disorder. Patient groups differed in most cortical clusters, with the strongest effects in sensory regions.
Limitations
Methodological concerns of in-scanner motion and the use of full correlation measures may make analyses more vulnerable to noise.
Conclusion
Our results show decreased eigenvector centrality of limbic structures in both patient groups and in sensory regions in patients with schizophrenia as well as increased centrality in frontal and parietal regions in both groups, with stronger effects in patients with schizophrenia.
doi:10.1503/jpn.150159
PMCID: PMC5008922  PMID: 26854755
17.  MicroRNA-326 acts as a molecular switch in the regulation of midbrain urocortin 1 expression 
Background
Altered levels of urocortin 1 (Ucn1) in the centrally projecting Edinger–Westphal nucleus (EWcp) of depressed suicide attempters or completers mediate the brain’s response to stress, while the mechanism regulating Ucn1 expression is unknown. We tested the hypothesis that microRNAs (miRNAs), which are vital fine-tuners of gene expression during the brain’s response to stress, have the capacity to modulate Ucn1 expression.
Methods
Computational analysis revealed that the Ucn1 3′ untranslated region contained a conserved binding site for miR-326. We examined miR-326 and Ucn1 levels in the EWcp of depressed suicide completers. In addition, we evaluated miR-326 and Ucn1 levels in the serum and the EWcp of a chronic variable mild stress (CVMS) rat model of behavioural despair and after recovery from CVMS, respectively. Gain and loss of miR-326 function experiments examined the regulation of Ucn1 by this miRNA in cultured midbrain neurons.
Results
We found reduced miR-326 levels concomitant with elevated Ucn1 levels in the EWcp of depressed suicide completers as well as in the EWcp of CVMS rats. In CVMS rats fully recovered from stress, both serum and EWcp miR-326 levels rebounded to nonstressed levels. While downregulation of miR-326 levels in primary midbrain neurons enhanced Ucn1 expression levels, miR-326 overexpression selectively reduced the levels of this neuropeptide.
Limitations
This study lacked experiments showing that in vivo alteration of miR-326 levels alleviate depression-like behaviours. We show only correlative data for miR-325 and cocaine- and amphetamine-regulated transcript levels in the EWcp.
Conclusion
We identified miR-326 dysregulation in depressed suicide completers and characterized this miRNA as an upstream regulator of the Ucn1 neuropeptide expression in midbrain neurons.
doi:10.1503/jpn.150154
PMCID: PMC5008923  PMID: 27045550
18.  Neural signature of behavioural inhibition in women with bulimia nervosa 
Background
Impaired inhibitory control is considered a behavioural phenotype in patients with bulimia nervosa. However, the underlying neural correlates of impaired general and food-specific behavioural inhibition are largely unknown. Therefore, we investigated brain activation during the performance of behavioural inhibition to general and food-related stimuli in adults with bulimia nervosa.
Methods
Women with bulimia and healthy control women underwent event-related fMRI while performing a general and a food-specific no-go task.
Results
We included 28 women with bulimia nervosa and 29 healthy control women in our study. On a neuronal level, we observed significant group differences in response to general no-go stimuli in women with bulimia nervosa with high symptom severity; compared with healthy controls, the patients showed reduced activation in the right sensorimotor area (postcentral gyrus, precentral gyrus) and right dorsal striatum (caudate nucleus, putamen).
Limitations
The present results are limited to adult women with bulimia nervosa. Furthermore, it remains unclear whether impaired behavioural inhibition in patients with this disorder are a cause or consequence of chronic illness.
Conclusion
Our findings suggest that diminished frontostriatal brain activation in patients with bulimia nervosa contribute to the severity of binge eating symptoms. Gaining further insight into the neural mechanisms of behavioural inhibition problems in individuals with this disorder may inform brain-directed treatment approaches and the development of response inhibition training approaches to improve inhibitory control in patients with bulimia nervosa. The present study does not support greater behavioural and neural impairments to food-specific behavioural inhibition in these patients.
doi:10.1503/jpn.150335
PMCID: PMC5008924  PMID: 27575858
19.  Managing the comorbidity of schizophrenia and ADHD 
doi:10.1503/jpn.150251
PMCID: PMC5008925  PMID: 27575859
21.  Deconstructing the mental health crisis: 5 uneasy pieces 
doi:10.1503/jpn.160101
PMCID: PMC4915930  PMID: 27332766
22.  Deconstructing the mental health crisis in only 2 pieces 
doi:10.1503/jpn.160103
PMCID: PMC4915931  PMID: 27332767
23.  Progranulin deficiency induces overactivation of WNT5A expression via TNF-α/NF-κB pathway in peripheral cells from frontotemporal dementia-linked granulin mutation carriers 
Background
Loss-of-function progranulin gene (GRN) mutations have been identified as the major cause of frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein 43 (TDP-43) pathology (frontotemporal lobar degeneration [FTLD]-TDP); however, little is known about the association between progranulin (PGRN) deficiency and neuronal loss in individuals with FTLD-TDP. Previously we reported enhanced proliferative activity associated with the activation of WNT5A/CDK6/pRb signalling in PGRN-deficient cells. The objective of this work was to elucidate the association between PGRN deficiency, WNT5A signalling and cell proliferation in immortalized lymphoblasts from carriers of the c.709–1G > A GRN mutation (asymptomatic and FTLD-TDP).
Methods
We assessed cell proliferation in carriers of the c.709–1G > A GRN gene mutation and controls without GRN mutation and without sign of neurologic degeneration by cell counting or using an MTT assay. We used a luciferase assay to measure the nuclear factor-κ (NF-κ) activity. We evaluated messenger RNA levels using quantitative real-time polymerase chain reaction and protein levels by immunoblotting. Co-immunoprecipitation was used to analyze the interaction between PGRN and its receptors.
Results
We enrolled 19 carriers of the GRN gene mutation and 10 controls in this study. The PGRN-deficient cells showed increased expression of WNT5A due to NF-κB signalling overactivation. We observed a competition between PGRN and tumour necrosis factor-α (TNF-α) for binding both TNF receptors (TNFR) I and II. Blocking NF-κB signalling using wedelolactone or specific antibodies against TNFRs inhibited WNT5A overexpression and proliferation of PGRN-deficient cells. Conversely, the activation of NF-κB signalling by TNF-α increased WNT5A-dependent proliferation of control cells.
Limitations
All cell lines were derived from individuals harboring the same splicing GRN mutation. Nevertheless, most of the known GRN mutations lead to haploinsufficiency of the protein.
Conclusion
Our results revealed an important role of NF-κB signalling in PGRN-associated FTLD-TDP and confirm that PGRN can bind to TNF-α receptors regulating the expression of WNT5A, suggesting novel targets for treatment of FTLD-TDP linked to GRN mutations.
doi:10.1503/jpn.150131
PMCID: PMC4915932  PMID: 26624524
24.  Cortical thickness, volume and surface area in patients with bipolar disorder types I and II 
Background
Bipolar disorder (BD) is a common chronic psychiatric disorder mainly characterized by episodes of mania, hypomania and depression. The disorder is associated with cognitive impairments and structural brain abnormalities, such as lower cortical volumes in primarily frontal brain regions than healthy controls. Although bipolar disorder types I (BDI) and II (BDII) exhibit different symptoms and severity, previous studies have focused on BDI. Furthermore, the most frequently investigated measure in this population is cortical volume. The aim of our study was to investigate abnormalities in patients with BDI and BDII by simultaneously analyzing cortical volume, thickness and surface area, which yields more information about disease- and symptom-related neurobiology.
Methods
We used MRI to measure cortical volume, thickness and area in patients with BDI and BDII as well as in healthy controls. The large study cohort enabled us to adjust for important confounding factors.
Results
We included 81 patients with BDI, 59 with BDII and 85 controls in our analyses. Cortical volume, thickness and surface area abnormalities were present in frontal, temporal and medial occipital regions in patients with BD. Lithium and antiepileptic drug use had an effect on the observed differences in medial occipital regions. Patients with the subtypes BDI and BDII displayed common cortical abnormalities, such as lower volume, thickness and surface area than healthy controls in frontal brain regions but differed in temporal and medial prefrontal regions, where only those with BDI had abnormally low cortical volume and thickness.
Limitations
The group differences can be explained by progressive changes, but also by premorbid conditions. They could also have been influenced by unknown factors, such as social, environmental or genetic factors.
Conclusion
Our findings suggest diagnosis-related neurobiological differences between the BD subtypes, which could explain distinct symptoms and point to potential biomarkers that could inform the subtype diagnosis of BD.
doi:10.1503/jpn.150093
PMCID: PMC4915933  PMID: 26645741
25.  Male veterans with PTSD exhibit aberrant neural dynamics during working memory processing: an MEG study 
Background
Posttraumatic stress disorder (PTSD) is associated with executive functioning deficits, including disruptions in working memory. In this study, we examined the neural dynamics of working memory processing in veterans with PTSD and a matched healthy control sample using magnetoencephalography (MEG).
Methods
Our sample of recent combat veterans with PTSD and demographically matched participants without PTSD completed a working memory task during a 306-sensor MEG recording. The MEG data were preprocessed and transformed into the time-frequency domain. Significant oscillatory brain responses were imaged using a beamforming approach to identify spatiotemporal dynamics.
Results
Fifty-one men were included in our analyses: 27 combat veterans with PTSD and 24 controls. Across all participants, a dynamic wave of neural activity spread from posterior visual cortices to left frontotemporal regions during encoding, consistent with a verbal working memory task, and was sustained throughout maintenance. Differences related to PTSD emerged during early encoding, with patients exhibiting stronger α oscillatory responses than controls in the right inferior frontal gyrus (IFG). Differences spread to the right supramarginal and temporal cortices during later encoding where, along with the right IFG, they persisted throughout the maintenance period.
Limitations
This study focused on men with combat-related PTSD using a verbal working memory task. Future studies should evaluate women and the impact of various traumatic experiences using diverse tasks.
Conclusion
Posttraumatic stress disorder is associated with neurophysiological abnormalities during working memory encoding and maintenance. Veterans with PTSD engaged a bilateral network, including the inferior prefrontal cortices and supramarginal gyri. Right hemispheric neural activity likely reflects compensatory processing, as veterans with PTSD work to maintain accurate performance despite known cognitive deficits associated with the disorder.
doi:10.1503/jpn.150058
PMCID: PMC4915934  PMID: 26645740

Results 1-25 (1559)