Impact of schizophrenia‐risk gene dysbindin 1 on brain activation in bilateral middle frontal gyrus during a working memory task in healthy individuals

Working memory (WM) dysfunction is a hallmark feature of schizophrenia. Functional imaging studies using WM tasks have documented both prefrontal hypo‐ and hyperactivation in schizophrenia. Schizophrenia is highly heritable, and it is unclear which susceptibility genes modulate WM and its neural correlates. A strong linkage between genetic variants in the dysbindin 1 gene and schizophrenia has been demonstrated. The aim of this study was to investigate the influence of the DTNBP1 schizophrenia susceptibility gene on WM and its neural correlates in healthy individuals. Fifty‐seven right‐handed, healthy male volunteers genotyped for DTNBP1 SNP rs1018381 status were divided in heterozygous risk‐allele carriers (T/C) and homozygous noncarriers (C/C). WM was assessed by a 2‐back vs. 0‐back version of the Continuous Performance Test (CPT), while brain activation was measured with fMRI. DTNBP1 SNP rs1018381 carrier status was determined and correlated with WM performance and brain activation. Despite any differences in behavioral performance, risk‐allele carriers exhibited significantly increased activation of the bilateral middle frontal gyrus (BA 9), a part of the dorsolateral prefrontal cortex (DLPFC), compared to noncarriers. This difference did not correlate with WM performance. The fMRI data provide evidence for an influence of genetic variation in DTNBP1 gene region tagged by SNP rs1018381 on bilateral middle frontal gyrus activation during a WM task. The increased activation in these brain areas may be a consequence of “inefficient” or compensatory DLPFC cognitive control functions. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto‐hippocampal connectivity

Background: Genome‐wide association studies have identified the rs1006737 single nucleotide polymorphism (SNP) in the CACNA1C gene as a susceptibility locus for schizophrenia and bipolar disorder. On the neural systems level this association is explained by altered functioning of the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF), brain regions also affected by mental illness. In the present study we investigated the association of rs1006737 genotype with prefrontal activation and fronto‐hippocampal connectivity. Methods: We used functional magnetic resonance imaging to measure neural activation during an n‐back working memory task in 94 healthy subjects. All subjects were genotyped for the SNP rs1006737. We tested associations of the rs1006737 genotype with changes in working‐memory‐related DLPFC activation and functional integration using a seed region functional connectivity approach. Results: Rs1006737 genotype was associated with altered right‐hemispheric DLPFC activation. The homozygous A (risk) group showed decreased activation compared to G‐allele carriers. Further, the functional connectivity analysis revealed a positive association of fronto‐hippocampal connectivity with rs1006737 A alleles. Conclusions: We did not replicate the previous findings of increased right DLPFC activation in CACNA1C rs1006737 A homozygotes. In fact, we found the opposite effect, thus questioning prefrontal inefficiency as rs1006737 genotype‐related intermediate phenotype. On the other hand, our results indicate that alterations in the functional coupling between the prefrontal cortex and the medial temporal lobe could represent a neural system phenotype that is mediated by CACNA1C rs1006737 and other genetic susceptibility loci for schizophrenia and bipolar disorder. Hum Brain Mapp 35:1190–1200, 2014. © 2013 Wiley Periodicals, Inc.     

Theta burst stimulation‐induced inhibition of dorsolateral prefrontal cortex reveals hemispheric asymmetry in striatal dopamine release during a set‐shifting task – a TMS–[11C]raclopride PET study

The prefrontostriatal network is considered to play a key role in executive functions. Previous neuroimaging studies have shown that executive processes tested with card‐sorting tasks requiring planning and set‐shifting [e.g. Montreal‐card‐sorting‐task (MCST)] may engage the dorsolateral prefrontal cortex (DLPFC) while inducing dopamine release in the striatum. However, functional imaging studies can only provide neuronal correlates of cognitive performance and cannot establish a causal relation between observed brain activity and task performance. In order to investigate the contribution of the DLPFC during set‐shifting and its effect on the striatal dopaminergic system, we applied continuous theta burst stimulation (cTBS) to left and right DLPFC. Our aim was to transiently disrupt its function and to measure MCST performance and striatal dopamine release during [¹¹C]raclopride PET. A significant hemispheric asymmetry was observed. cTBS of the left DLPFC impaired MCST performance and dopamine release in the ipsilateral caudate–anterior putamen and contralateral caudate nucleus, as compared to cTBS of the vertex (control). These effects appeared to be limited only to left DLPFC stimulation while right DLPFC stimulation did not influence task performance or [¹¹C]raclopride binding potential in the striatum. This is the first study showing that cTBS, by disrupting left prefrontal function, may indirectly affect striatal dopamine neurotransmission during performance of executive tasks. This cTBS‐induced regional prefrontal effect and modulation of the frontostriatal network may be important for understanding the contribution of hemisphere laterality and its neural bases with regard to executive functions, as well as for revealing the neurochemical substrate underlying cognitive deficits.     

Intact working memory in non‐manifesting LRRK2 carriers – an fMRI study

Cognitive impairments are prevalent in patients with Parkinson's disease. Mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene are the most common cause of genetic Parkinsonism. Non‐manifesting carriers of the G2019S mutation in the LRRK2 gene were found to have lower executive functions as measured by the Stroop task. This exploratory study aimed to assess whether the cognitive impairment in non‐manifesting carriers is specific for executive functions or includes other cognitive domains such as working memory. We recruited 77 non‐manifesting first‐degree relatives of Parkinson's disease patients (38 carriers). A block‐design fMRI N‐back task, with 0‐back, 2‐back and 3‐back conditions, was used in order to assess working memory. Participants were well matched on the Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test, Unified Parkinson's Disease Rating Scale part III, digit span, age, gender and Beck Depression Inventory. The task achieved the overall expected effect in both groups with longer reaction times and lower accuracy rates with increasing task demands. However, no whole‐brain or region‐of‐interest between‐groups differences were found on any of the task conditions. These results indicate that non‐manifesting carriers of the G2019S mutation in the LRRK2 gene have a specific cognitive profile with executive functions, as assessed by the Stroop task, demonstrating significant impairment but with working memory, as assessed with the N‐back task, remaining relatively intact. These finding shed light on the pre‐motor cognitive changes in this unique ‘at risk’ population and should enable more focused cognitive assessments of these cohorts.     

Unilateral Prefrontal Direct Current Stimulation Effects are Modulated by Working Memory Load and Gender

BackgroundRecent studies revealed that anodal transcranial direct current stimulation (tDCS) to the left dorsolateral prefrontal cortex (DLPFC) may improve verbal working memory (WM) performance in humans. In the present study, we evaluated executive attention, which is the core of WM capacity, considered to be significantly involved in tasks that require active maintenance of memory representations in interference-rich conditions, and is highly dependent on DLPFC function.ObjectivesWe investigated verbal WM accuracy using a WM task that is highly sensitive to executive attention function. We were interested in how verbal WM accuracy may be affected by WM load, unilateral DLPFC stimulation, and gender, as previous studies showed gender-dependent brain activation during verbal WM tasks.MethodsWe utilized a modified verbal n-Back task hypothesized to increase demands on executive attention. We examined “online” WM performance while participants received transcranial direct current stimulation (tDCS), and implicit learning performance in a post-stimulation WM task.ResultsSignificant lateralized “online” stimulation effects were found only in the highest WM load condition revealing that males benefit from left DLPFC stimulation, while females benefit from right DLPFC stimulation. High WM load performance in the left DLPFC stimulation was significantly related to post-stimulation recall performance.ConclusionsOur findings support the idea that lateralized stimulation effects in high verbal WM load may be gender-dependent. Further, our post-stimulation results support the idea that increased left hemisphere activity may be important for encoding verbal information into episodic memory as well as for facilitating retrieval of context-specific targets from semantic memory.     

Screening diagnosis of executive dysfunction after ischemic stroke and the effects of transcranial magnetic stimulation: A prospective functional near-infrared spectroscopy study

Background

Post-ischemic stroke executive impairment (PISEI) is a serious obstacle for patients to returning to their society and is currently difficult to screen early and clinically ineffective.

Aim

The aim of the study was to clarify whether functional near-infrared spectroscopy (fNIRS) can be used as a rapid screening tool for PISEI and to explore the efficacy of transcranial magnetic stimulation (TMS) in PISEI patients and the changes in brain function.

Methods

A single-blind, randomized controlled study design was used to detect hemodynamic differences by fNIIRS in 16 PISEI patients and 16 healthy subjects during the resting state and Stroop task, respectively. After 3 days, all subjects received a single TMS intervention and underwent simultaneous fNIRS testing for the Stroop task before and 3 days after the TMS intervention.

Results

PISEI patients had significantly higher HbO₂ content in the left dorsolateral prefrontal cortex (DLPFC), the right pre-motor cortex (PMC) and the right primary sensorimotor cortex (SM1) during the Stroop task compared to the resting state (F = 141.966, p < 0.001), but significantly lower than healthy subjects (T = −3.413, p = 0.002). After TMS intervention, PISEI patients' time and error number scores on the Stroop test were significantly enhanced, and the functional activity of the above-mentioned brain regions was significantly more active than at baseline, while the strength of their functional connections with each other was markedly increased.

Conclusions

fNIRS helped screen and diagnose PISEI. A single TMS session benefited PISEI patients with effects lasting 3 days, which may be attributed to activation of the left DLPFC, right PMC and right SM1 brain regions.     

Genetic risk mechanisms of posttraumatic stress disorder in the human brain

Posttraumatic stress disorder (PTSD) follows exposure to a traumatic event in susceptible individuals. Recently, genome‐wide association studies have identified a number of genetic sequence variants that are associated with the risk of developing PTSD. To follow up on identifying the molecular mechanisms of these risk variants, we performed genotype to RNA sequencing–derived quantitative expression (whole gene, exon, and exon junction levels) analysis in the dorsolateral prefrontal cortex (DLPFC) of normal postmortem human brains. We further investigated genotype–gene expression associations within the amygdala in a smaller independent RNA sequencing (Genotype‐Tissue Expression [GTEx]) dataset. Our DLPFC analyses identified significant expression quantitative trait loci (eQTL) associations for a “candidate” PTSD risk SNP rs363276 and the expression of two genes: SLC18A2 and PDZD8, where the PTSD risk/minor allele T was associated with significantly lower levels of gene expression for both genes, in the DLPFC. These eQTL associations were independently confirmed in the amygdala from the GTEx database. Rs363276 “T” carriers also showed significantly increased activity in the amygdala during an emotional face‐matching task in healthy volunteers. Taken together, our preliminary findings in normal human brains represent a tractable approach to identify mechanisms by which genetic variants potentially increase an individual's risk for developing PTSD. © 2016 Wiley Periodicals, Inc.     

Practice on conflict tasks promotes executive function of working memory in the elderly

Effects of practice on a conflict task in elderly individuals are examined with a focus on its impact on executive function in working memory. During a short-term practice period, healthy elderly participants practiced switching attention using a Stroop task that involved a conflict between a task relevant stimulus and an irrelevant stimulus. To explore neural substrates underlying practice effects, two working memory tasks were used: a focus reading span test (F-RST) and a non-focus reading span test (NF-RST); the NF-RST test demanded greater switching attention due to a conflict between the relevant task stimulus and an irrelevant task stimulus, thus requiring an attention switch from the latter to the former. Following the Stroop task practice, fMRI data showed that participants who had engaged in practice had significant increases in activation in the anterior cingulate cortex (ACC), the left inferior parietal lobule (IPL), the left dorsolateral prefrontal cortex (DLPFC) and the precuneus regions during the NF-RST. By contrast, a control group, which did not practice, showed no significant increases in these regions. Results suggest that practice on conflict tasks in elderly individuals activated regions related to conflict perceiving and attention switching regions as well as attention-maintenance regions thereby improving performance on tasks requiring a high degree of attention control of working memory.     

FMRI correlates of the WAIS-III symbol search subtest.

Functional magnetic resonance imaging (FMRI) experiments frequently administer substantially adapted cognitive tests. This study was designed to identify FMRI correlates of a well-standardized clinical measure presented with minor adaptations. We administered the WAIS-III Symbol Search (SS) and a visuospatial control task to fifteen adults during FMRI. SS-related brain activity was identified, followed by analyses of activity related to performance level. Compared to the control task, SS was associated with greater activity in bilateral medial occipital, occipitoparietal, occipitotemporal, parietal, and dorsolateral prefrontal cortices (DLPFC). Across both tasks, slower processing speed was also related to greater activity in these areas, except right DLPFC. Greater activity in left DLPFC was specifically related to slower processing speed during SS. Performance was consistent with education levels. Findings suggest that SS performance involves regions associated with executive and visual processing. Furthermore, slower SS performance was related to greater recruitment of left hemisphere regions associated with executive function in other studies.     

Dysfunction of the Left Dorsolateral Prefrontal Cortex is Primarily Responsible for Impaired Attentional Processing in Schizophrenia

Objective

The results for finding the deficit in the anterior cingulate (ACC) in schizophrenic patients (SZ) have been inconsistent according to the studies that used different Stroop tasks, which is unlike the deficit in the dorsolateral prefrontal cortex (DLPFC). In order to explore for the core region that''s responsible for the selective attention deficit in SZ, we examined the results of a functional neuroimaging study, which involved the performance of the Stroop task using high or low prefrontal cortex related loads in SZ.

Methods

Ten schizophrenic patients and healthy controls (HC) received functional magnetic resonance imaging (fMRI) during a Short/Long-term latency Stroop task. The changes in the neural activity were determined in well-known Stroop related regions of interest (ROIs) that consisted of the DLPFC, ACC, the parietal lobule and in the whole brain regions for both the main and interaction effects of latency, and the results of the short-term and long-term latency Stroop conditions were compared.

Results

The response times for both the congruency and latency effects were more prolonged in the schizophrenics than in the HC. For the congruency effect, the schizophrenics showed significantly less activation in the same site of the left DLPFC in both the short-term and long-term latency conditions, as compared with the HC. For the latency effect, the regions of the left-side language network were over- or under-activated in the schizophrenics, as compared with the HC. Any interaction effect was not found for both the behavioral and fMRI results.

Conclusion

Our results indicate that the deficit in the left DLPFC is the core impairment of attentional processing in schizophrenics, regardless of other possible interactions such as the latency effect.     

Reduced neural connectivity but increased task‐related activity during working memory in de novo Parkinson patients

Objective: Patients with Parkinson's disease (PD) often suffer from impairments in executive functions, such as working memory deficits. It is widely held that dopamine depletion in the striatum contributes to these impairments through decreased activity and connectivity between task‐related brain networks. We investigated this hypothesis by studying task‐related network activity and connectivity within a sample of de novo patients with PD, versus healthy controls, during a visuospatial working memory task. Methods: Sixteen de novo PD patients and 35 matched healthy controls performed a visuospatial n‐back task while we measured their behavioral performance and neural activity using functional magnetic resonance imaging. We constructed regions‐of‐interest in the bilateral inferior parietal cortex (IPC), bilateral dorsolateral prefrontal cortex (DLPFC), and bilateral caudate nucleus to investigate group differences in task‐related activity. We studied network connectivity by assessing the functional connectivity of the bilateral DLPFC and by assessing effective connectivity within the frontoparietal and the frontostriatal networks. Results: PD patients, compared with controls, showed trend‐significantly decreased task accuracy, significantly increased task‐related activity in the left DLPFC and a trend‐significant increase in activity of the right DLPFC, left caudate nucleus, and left IPC. Furthermore, we found reduced functional connectivity of the DLPFC with other task‐related regions, such as the inferior and superior frontal gyri, in the PD group, and group differences in effective connectivity within the frontoparietal network. Interpretation: These findings suggest that the increase in working memory‐related brain activity in PD patients is compensatory to maintain behavioral performance in the presence of network deficits. Hum Brain Mapp 36:1554–1566, 2015. © 2015 Wiley Periodicals, Inc.     

A specific pattern of executive dysfunctions in transcortical motor aphasia

Background: Recent studies imply that executive functions (EF) are closely related to our ability to comprehend and produce language. A number of findings suggest that functional communication and language recovery in aphasia depend not only on intact language abilities but on EF as well. Some patients with transcortical motor aphasia (TMA) show language deficits only in tasks in which conflicting representations must be resolved by executive processes. In line with these results, others have proposed that TMA should be referred to as “dysexecutive aphasia”. EF in aphasia have mostly been studied using neuropsychological tests, therefore there is a need for systematic experimental investigations of these skills.

Aims: 1. To investigate EF in TMA, and to test whether executive dysfunctions are specific to TMA. 2. To experimentally measure different components of EF: updating working memory representations and inhibition of prepotent responses.

Methods & Procedures: Five individuals with TMA, five patients with conduction aphasia and ten healthy controls participated. We designed four nonverbal tasks: to measure updating of working memory representations, we used a visual and an auditory n-back task. To assess inhibition of prepotent responses, we designed a Stop-signal and a nonverbal Stroop task. All tasks involved within-subject baseline conditions.

Outcomes & Results: We found certain EF deficits in both groups of individuals with aphasia as compared to healthy controls. Individuals with TMA showed impaired inhibition as indexed by the Stop-signal and the nonverbal Stroop tasks, as well as a deficit of updating of working memory representations as indexed by the auditory n-back task. Participants with conduction aphasia had difficulties in only one of the tasks measuring inhibition, but no clear evidence for impairment of updating of working memory representations was found.

Conclusions: Although the results show different patterns of EF deficits in the groups with aphasia, the findings clearly demonstrate that EF deficits are not specific to participants with TMA. Based on these results, and on earlier data highlighting the role of executive processes in functional communication and language recovery, we suggest that tests of EF should be an inherent part of clinical aphasia assessment.     

Plasma neuropeptide Y: a biomarker for symptom severity in chronic fatigue syndrome

Background

Attention deficits belong to the main cognitive symptoms of schizophrenia and come along with altered neural activity in previously described cerebral networks. Given the high heritability of schizophrenia the question arises if impaired function of these networks is modulated by susceptibility genes and detectable in healthy risk allele carriers.

Methods

The present event-related fMRI study investigated the effect of the single nucleotide polymorphism (SNP) rs1018381 of the DTNBP1 (dystrobrevin-binding protein 1) gene on brain activity in 80 subjects while performing the attention network test (ANT). In this reaction time task three domains of attention are probed simultaneously: alerting, orienting and executive control of attention.

Results

Risk allele carriers showed impaired performance in the executive control condition associated with reduced neural activity in the left superior frontal gyrus [Brodmann area (BA) 9]. Risk allele carriers did not show alterations in the alerting and orienting networks.

Conclusions

BA 9 is a key region of schizophrenia pathology and belongs to a network that has been shown previously to be involved in impaired executive control mechanisms in schizophrenia. Our results identified the impact of DTNBP1 on the development of a specific attention deficit via modulation of a left prefrontal network.     

Neuroimaging of marijuana smokers during inhibitory processing: a pilot investigation

Neuropsychological investigations of substance abusers have reported impairments on tasks mediated by the frontal executive system, including functions associated with behavioral inhibition and decision making. The higher order or executive components which are involved in decision making include selective attention and short term storage of information, inhibition of response to irrelevant information, initiation of response to relevant information, self-monitoring of performance, and changing internal and external contingencies in order to "stay the course" towards the ultimate goal. Given the hypothesized role of frontal systems in decision making and the previous evidence that executive dysfunctions and structural brain changes exist in subjects who use illicit drugs, we applied fMRI and diffusion tensor imaging (DTI) techniques in a pilot investigation of heavy cannabis smokers and matched control subjects while performing a modification of the classic Stroop task. Marijuana smokers demonstrated significantly lower anterior cingulate activity in focal areas of the anterior cingulate cortex and higher midcingulate activity relative to controls, although both groups were able to perform the task within normal limits. Normal controls also demonstrated increased activity within the right dorsolateral prefrontal cortex (DLPFC) during the interference condition, while marijuana smokers demonstrated a more diffuse, bilateral pattern of DLPFC activation. Similarly, although both groups performed the task well, marijuana smokers made more errors of commission than controls during the interference condition, which were associated with different brain regions than control subjects. These findings suggest that marijuana smokers exhibit different patterns of BOLD response and error response during the Stroop interference condition compared to normal controls despite similar task performance. Furthermore, DTI measures in frontal regions, which include the genu and splenium of the corpus callosum and bilateral anterior cingulate white matter regions, showed no between group differences in fractional anisotropy (FA), a measure of directional coherence within white matter fiber tracts, but a notable increase in trace, a measure of overall isotropic diffusivity in marijuana smokers compared to controls. Overall, results from the present study indicate significant differences in the magnitude and pattern of signal intensity change within the anterior cingulate and the DLPFC during the Stroop interference subtest in chronic marijuana smokers compared to normal controls. Furthermore, although chronic marijuana smokers were able to perform the task reasonably well, the functional activation findings suggest they utilize different cortical processes from the control subjects in order to do so. Findings from this study are consistent with the notion that substance abusers demonstrate evidence of altered frontal neural function during the performance of tasks that involve inhibition and performance monitoring, which may affect the ability to make decisions.     

APOE influences working memory in non‐demented elderly through an interaction with SPON1 rs2618516

Exploring how risk genes cumulatively impair brain function in preclinical phase (i.e., in cognitively normal elderly) could provide critical insights into the pathophysiology of Alzheimer's disease (AD). Working memory impairment has always been a considerable cognitive deficit in AD, which is likely under complex genetic control. Though, the APOE ?4 allele could damage the working memory performance in normal elderly, dissociable results have been reported. This allele may exert specific effects in contexts with other genetic variants. The rs2618516 in the spondin 1 gene (SPON1) has been associated with AD risk and brain structure in the elderly. SPON1 may interact with APOE through processing the amyloid precursor protein and suppressing amyloid‐β levels. Using neuropsychological tasks from 710 individuals, we found significant SPON1 × APOE genotype interactions in working memory and executive function performances. Moreover, such interaction was also found in regional brain activations based on functional magnetic resonance imaging data with the n‐back working memory task performed in a sub‐cohort of 64 subjects. The effects of ?4 allele on activation of right inferior frontal gyrus, triangular part (IFGtriang.R) were modulated by rs2618516 in a working memory task. Furthermore, lower IFGtriang.R activation was associated with better cognitive functions. Moreover, the IFGtriang.R activation could mediate the impacts of SPON1 × APOE interactions on working memory performance. These findings suggested the importance of weighing APOE effects on brain activation under the working memory task within the context of the SPON1 genotype.     

Piccolo genotype modulates neural correlates of emotion processing but not executive functioning

Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome-wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene—involved in monoaminergic neurotransmission—as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD.     

Abnormalities of the executive control network in multiple sclerosis phenotypes: An fMRI effective connectivity study

The Stroop interference task is a cognitively demanding task of executive control, a cognitive ability that is often impaired in patients with multiple sclerosis (MS). The aim of this study was to compare effective connectivity patterns within a network of brain regions involved in the Stroop task performance between MS patients with three disease clinical phenotypes [relapsing‐remitting (RRMS), benign (BMS), and secondary progressive (SPMS)] and healthy subjects. Effective connectivity analysis was performed on Stroop task data using a novel method based on causal Bayes networks. Compared with controls, MS phenotypes were slower at performing the task and had reduced performance accuracy during incongruent trials that required increased cognitive control. MS phenotypes also exhibited connectivity abnormalities reflected as weaker shared connections, presence of extra connections (i.e., connections absent in the HC connectivity pattern), connection reversal, and loss. In SPMS and the BMS groups but not in the RRMS group, extra connections were associated with deficits in the Stroop task performance. In the BMS group, the response time associated with correct responses during the congruent condition showed a positive correlation with the left posterior parietal → dorsal anterior cingulate connection. In the SPMS group, performance accuracy during the congruent condition showed a negative correlation with the right insula → left insula connection. No associations between extra connections and behavioral performance measures were observed in the RRMS group. These results suggest that, depending on the phenotype, patients with MS use different strategies when cognitive control demands are high and rely on different network connections. Hum Brain Mapp, 37:2293–2304, 2016. © 2016 Wiley Periodicals, Inc.     

Analysis of association between common variants in the SLCO6A1 gene with schizophrenia,bipolar disorder and major depressive disorder in the Han Chinese population

Objectives The SLCO6A1 gene belongs to a superfamily of genes which is known to be a solute carrier family of OATPs (SLCO). The SLCO6A1 gene encodes OATP6A1 protein in humans. A previous genome-wide association study (GWAS) of schizophrenia conducted in the Swedish population demonstrated a significant association of rs6878284, which is located in the SLCO6A1 gene, with schizophrenia. To further investigate whether this gene is also a risk locus for schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD) in the Han Chinese population, a case–control study was designed. Methods In total 1,248 unrelated SCZ cases, 1,344 BPD cases, 1,056 unrelated MDD cases and 1,248 normal controls were analysed in this study. We genotyped five SNPs using the Sequenom MassARRAY platform. Results We found no association of rs6878284 with SCZ [Corrected P_allele?=?0.969, Corrected P_genotype?=?0.997]. Furthermore, we found a statistically significant association of the rs7734060 genotype with MDD after correction [rs7734060: Corrected P_allele?=?0.114, Corrected P_genotype?=?0.036] in the Han Chinese population. Conclusions This is the first study which reveals no association of rs6878284 with SCZ and also predicts that rs7734060 could be a risk locus for MDD in the Han Chinese population.     

COMT Val158Met polymorphism influences the susceptibility to framing in decision‐making: OFC‐amygdala functional connectivity as a mediator

Individuals tend to avoid risk in a gain frame, in which options are presented in a positive way, but seek risk in a loss frame, in which the same options are presented negatively. Previous studies suggest that emotional responses play a critical role in this “framing effect.” Given that the Met allele of COMT Val158Met polymorphism (rs4680) is associated with the negativity bias during emotional processing, this study investigated whether this polymorphism is associated with individual susceptibility to framing and which brain areas mediate this gene–behavior association. Participants were genotyped, scanned in resting state, and completed a monetary gambling task with options (sure vs risky) presented as potential gains or losses. The Met allele carriers showed a greater framing effect than the Val/Val homozygotes as the former gambled more than the latter in the loss frame. Moreover, the gene–behavior association was mediated by resting‐state functional connectivity (RSFC) between orbitofrontal cortex (OFC) and bilateral amygdala. Met allele carriers showed decreased RSFC, thereby demonstrating higher susceptibility to framing than Val allele carriers. These findings demonstrate the involvement of COMT Val158Met polymorphism in the framing effect in decision‐making and suggest RSFC between OFC and amygdala as a neural mediator underlying this gene–behavior association. Hum Brain Mapp 37:1880–1892, 2016. © 2016 Wiley Periodicals, Inc .     

Precuneus degeneration in nondemented elderly individuals with APOE ɛ4: Evidence from structural and functional MRI analyses

Neurodegenerative diseases such as Alzheimer's disease (AD) have been recognized to exhibit disease‐specific brain vulnerability patterns. Apolipoprotein E (APOE ) ?4 allele imparts a high genetic risk of developing AD. Whether the APOE ?4 allele damages the brain when cognitive functions are still intact is important to understand, especially for possible early detection and intervention. This study aimed to examine the selective degeneration pattern associated with the APOE ?4 allele in the brains of cognitively normal elderly subjects. We enrolled 35 cognitively healthy ?4 carriers and 40 non‐carriers (53 to 81 years old) to evaluate group differences in cortical thickness and brain activation during a memory‐encoding task. We also assessed the functional connectivity of the brain regions with both structural and functional damages. The results from the neuropsychological tests showed that the performances of ?4 carriers and non‐carriers were comparable. Primarily, we found that the precuneus exhibited thinner cortical thickness and decreased deactivation during memory encoding. Furthermore, the connectivity analyses show that carriers exhibited damaged connectivity of the precuneus to several regions in the default mode network and the attention/executive control network. Our study reveals the degeneration pattern of the ?4 allele, which could be used as a potential biomarker for early detection for possible interventions and treatments. Hum Brain Mapp 38:271–282, 2017 . © 2016 Wiley Periodicals, Inc.