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.     

Impairments in musical abilities reflected in the auditory brainstem: evidence from congenital amusia

Congenital amusia is a neurogenetic condition, characterized by a deficit in music perception and production, not explained by hearing loss, brain damage or lack of exposure to music. Despite inferior musical performance, amusics exhibit normal auditory cortical responses, with abnormal neural correlates suggested to lie beyond auditory cortices. Here we show, using auditory brainstem responses to complex sounds in humans, that fine‐grained automatic processing of sounds is impoverished in amusia. Compared with matched non‐musician controls, spectral amplitude was decreased in amusics for higher harmonic components of the auditory brainstem response. We also found a delayed response to the early transient aspects of the auditory stimulus in amusics. Neural measures of spectral amplitude and response timing correlated with participants' behavioral assessments of music processing. We demonstrate, for the first time, that amusia affects how complex acoustic signals are processed in the auditory brainstem. This neural signature of amusia mirrors what is observed in musicians, such that the aspects of the auditory brainstem responses that are enhanced in musicians are degraded in amusics. By showing that gradients of music abilities are reflected in the auditory brainstem, our findings have implications not only for current models of amusia but also for auditory functioning in general.     

Alterations of fronto-temporal connectivity during word encoding in schizophrenia

Cognitive deficits, including impaired verbal memory, are prominent in schizophrenia and lead to increased disability. Functional neuroimaging of patients with schizophrenia performing memory tasks has revealed abnormal activation patterns in prefrontal cortex and temporo-limbic regions. Aberrant fronto-temporal interactions thus represent a potential pathophysiological mechanism underlying verbal memory deficits, yet this hypothesis of disturbed connectivity is not tested directly with standard activation studies. We performed within-subject correlations of frontal and temporal timeseries to measure functional connectivity during verbal encoding. Our results confirm earlier findings of aberrant fronto-temporal connectivity in schizophrenia, and extend them by identifying distinct alterations within dorsal and ventral prefrontal cortex. Relative to healthy controls, patients with schizophrenia had reduced connectivity between the dorsolateral prefrontal cortex (DLPFC) and temporal lobe areas including parahippocampus and superior temporal gyrus. In contrast, patients showed increased connectivity between a region of ventrolateral prefrontal cortex (VLPFC) and these same temporal lobe regions. Higher temporal-DLPFC connectivity during encoding was associated with better subsequent recognition accuracy in controls, but not patients. Temporal-VLPFC connectivity was uncorrelated with recognition accuracy in either group. The results suggest that reduced temporal-DLPFC connectivity in schizophrenia could underlie encoding deficits, and increased temporal-VLPFC connectivity may represent an ineffective compensatory effort.     

Fronto‐parietal and temporal brain dysfunction in depression: A fMRI investigation of auditory mismatch processing

Mismatch responses reflect neural mechanisms of early cognitive processing in the auditory domain. Disturbances of these mechanisms on multiple levels of neural processing may contribute to clinical symptoms in major depression (MD). A functional magnetic resonance imaging (fMRI) study was conducted to identify neurobiological foundations of altered mismatch processing in MD. Twenty‐five patients with major depression and 25 matched healthy individuals completed an auditory mismatch paradigm optimized for fMRI. Brain activity during mismatch processing was compared between groups. Moreover, seed‐based connectivity analyses investigated depression‐specific brain networks. In patients, mismatch processing was associated with reduced activation in the right auditory cortex as well as in a fronto‐parietal attention network. Moreover, functional coupling between the right auditory cortex and frontal areas was reduced in patients. Seed‐to voxel analysis on the whole‐brain level revealed reduced connectivity between the auditory cortex and the thalamus as well as posterior cingulate. The present study indicates deficits in sensory processing on the level of the auditory cortex in depression. Hyposensitivity in a fronto‐parietal network presumably reflects altered attention mechanisms in depression. The observed impairments may contribute to psychopathology by reducing the ability of the affected individuals to orient attention toward important environmental cues.     

Modulating neural oscillations by transcranial static magnetic field stimulation of the dorsolateral prefrontal cortex: A crossover,double‐blind,sham‐controlled pilot study

Transcranial static magnetic field stimulation (tSMS) is a novel non‐invasive brain stimulation technique that has been shown to locally increase alpha power in the parietal and occipital cortex. We investigated if tSMS locally increased alpha power in the left or right prefrontal cortex, as the balance of left/right prefrontal alpha power (frontal alpha asymmetry) has been linked to emotional processing and mood disorders. Therefore, altering frontal alpha asymmetry with tSMS may serve as a novel treatment to psychiatric diseases. We performed a crossover, double‐blind, sham‐controlled pilot study to assess the effects of prefrontal tSMS on neural oscillations. Twenty‐four right‐handed healthy participants were recruited and received left dorsolateral prefrontal cortex (DLPFC) tSMS, right DLPFC tSMS, and sham tSMS in a randomized order. Electroencephalography data were collected before (2 min eyes‐closed, 2 min eyes‐open), during (10 min eyes‐open), and after (2 min eyes‐open) stimulation. In contrast with our hypothesis, neither left nor right tSMS locally increased frontal alpha power. However, alpha power increased in occipital cortex during left DLPFC tSMS. Right DLPFC tSMS increased post‐stimulation fronto‐parietal theta power, indicating possible relevance to memory and cognition. Left and right DLPFC tSMS increased post‐stimulation left hemisphere beta power, indicating possible changes to motor behavior. Left DLPFC tSMS also increased post‐stimulation right frontal beta power, demonstrating complex network effects that may be relevant to aggressive behavior. We concluded that DLPFC tSMS modulated the network oscillations in regions distant from the location of stimulation and that tSMS has region specific effects on neural oscillations.     

Distinct neural substrates for visual short‐term memory of actions

Fundamental theories of human cognition have long posited that the short‐term maintenance of actions is supported by one of the “core knowledge” systems of human visual cognition, yet its neural substrates are still not well understood. In particular, it is unclear whether the visual short‐term memory (VSTM) of actions has distinct neural substrates or, as proposed by the spatio‐object architecture of VSTM, shares them with VSTM of objects and spatial locations. In two experiments, we tested these two competing hypotheses by directly contrasting the neural substrates for VSTM of actions with those for objects and locations. Our results showed that the bilateral middle temporal cortex (MT) was specifically involved in VSTM of actions because its activation and its functional connectivity with the frontal–parietal network (FPN) were only modulated by the memory load of actions, but not by that of objects/agents or locations. Moreover, the brain regions involved in the maintenance of spatial location information (i.e., superior parietal lobule, SPL) was also recruited during the maintenance of actions, consistent with the temporal–spatial nature of actions. Meanwhile, the frontoparietal network (FPN) was commonly involved in all types of VSTM and showed flexible functional connectivity with the domain‐specific regions, depending on the current working memory tasks. Together, our results provide clear evidence for a distinct neural system for maintaining actions in VSTM, which supports the core knowledge system theory and the domain‐specific and domain‐general architectures of VSTM.     

Neuroarchitecture of verbal and tonal working memory in nonmusicians and musicians

Working memory (WM) for auditory information has been thought of as a unitary system, but whether WM for verbal and tonal information relies on the same or different functional neuroarchitectures has remained unknown. This fMRI study examines verbal and tonal WM in both nonmusicians (who are trained in speech, but not in music) and highly trained musicians (who are trained in both domains). The data show that core structures of WM are involved in both tonal and verbal WM (Broca's area, premotor cortex, pre‐SMA/SMA, left insular cortex, inferior parietal lobe), although with significantly different structural weightings, in both nonmusicians and musicians. Additionally, musicians activated specific subcomponents only during verbal (right insular cortex) or only during tonal WM (right globus pallidus, right caudate nucleus, and left cerebellum). These results reveal the existence of two WM systems in musicians: A phonological loop supporting rehearsal of phonological information, and a tonal loop supporting rehearsal of tonal information. Differences between groups for tonal WM, and between verbal and tonal WM within musicians, were mainly related to structures involved in controlling, programming and planning of actions, thus presumably reflecting differences in action‐related sensorimotor coding of verbal and tonal information. Hum Brain Mapp 32:771–783, 2011. © 2010 Wiley‐Liss, Inc.     

Processing melodic contour and speech intonation in congenital amusics with Mandarin Chinese

Congenital amusia is a disorder in the perception and production of musical pitch. It has been suggested that early exposure to a tonal language may compensate for the pitch disorder (Peretz, 2008). If so, it is reasonable to expect that there would be different characterizations of pitch perception in music and speech in congenital amusics who speak a tonal language, such as Mandarin. In this study, a group of 11 adults with amusia whose first language was Mandarin were tested with melodic contour and speech intonation discrimination and identification tasks. The participants with amusia were impaired in discriminating and identifying melodic contour. These abnormalities were also detected in identifying both speech and non-linguistic analogue derived patterns for the Mandarin intonation tasks. In addition, there was an overall trend for the participants with amusia to show deficits with respect to controls in the intonation discrimination tasks for both speech and non-linguistic analogues. These findings suggest that the amusics’ melodic pitch deficits may extend to the perception of speech, and could potentially result in some language deficits in those who speak a tonal language.     

Effective connectivity during episodic memory retrieval in schizophrenia participants before and after antipsychotic medication

Background: Impairment in episodic memory is one of the most robust findings in schizophrenia. Disruptions of fronto‐temporal functional connectivity that could explain some aspects of these deficits have been reported. Recent work has identified abnormal hippocampal function in unmedicated patients with schizophrenia (SZ), such as increased metabolism and glutamate content that are not always seen in medicated SZ. For these reasons, we hypothesized that altered fronto‐temporal connectivity might originate from the hippocampus and might be partially restored by antipsychotic medication. Methods: Granger causality methods were used to evaluate the effective connectivity between frontal and temporal regions in 21 unmedicated SZ and 20 matched healthy controls (HC) during performance of an episodic memory retrieval task. In 16 SZ, effective connectivity between these regions was evaluated before and after 1‐week of antipsychotic treatment. Results: In HC, significant effective connectivity originating from the right hippocampus to frontal regions was identified. Compared to HC, unmedicated SZ showed significant altered fronto‐temporal effective connectivity, including reduced right hippocampal to right medial frontal connectivity. After 1‐week of antipsychotic treatment, connectivity more closely resembled the patterns observed in HC, including increased effective connectivity from the right hippocampus to frontal regions. Conclusions: These results support the notion that memory disruption in schizophrenia might originate from hippocampal dysfunction and that medication restores some aspects of fronto‐temporal dysconnectivity. Patterns of fronto‐temporal connectivity could provide valuable biomarkers to identify new treatments for the symptoms of schizophrenia, including memory deficits. Hum Brain Mapp 36:1442–1457, 2015. © 2014 Wiley Periodicals, Inc.     

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.     

Intonation processing increases task‐specific fronto‐temporal connectivity in tonal language speakers

Language comprehension depends on tight functional interactions between distributed brain regions. While these interactions are established for semantic and syntactic processes, the functional network of speech intonation – the linguistic variation of pitch – has been scarcely defined. Particularly little is known about intonation in tonal languages, in which pitch not only serves intonation but also expresses meaning via lexical tones. The present study used psychophysiological interaction analyses of functional magnetic resonance imaging data to characterise the neural networks underlying intonation and tone processing in native Mandarin Chinese speakers. Participants categorised either intonation or tone of monosyllabic Mandarin words that gradually varied between statement and question and between Tone 2 and Tone 4. Intonation processing induced bilateral fronto‐temporal activity and increased functional connectivity between left inferior frontal gyrus and bilateral temporal regions, likely linking auditory perception and labelling of intonation categories in a phonological network. Tone processing induced bilateral temporal activity, associated with the auditory representation of tonal (phonemic) categories. Together, the present data demonstrate the breadth of the functional intonation network in a tonal language including higher‐level phonological processes in addition to auditory representations common to both intonation and tone.     

Effective connectivity of the multiplication network: A functional MRI and multivariate granger causality mapping study

Developmental neuropsychology and functional neuroimaging evidence indicates that simple and complex mental calculation is subserved by a fronto‐parietal network. However, the effective connectivity (connection direction and strength) among regions within the fronto‐parietal network is still unexplored. Combining event‐related fMRI and multivariate Granger Causality Mapping (GCM), we administered a multiplication verification task to healthy participants asking them to solve single and double‐digit multiplications. The goals of our study were first, to identify the effective connectivity of the multiplication network, and second, to compare the effective connectivity patterns between a low and a high arithmetical competence (AC) group. The manipulation of multiplication difficulty revealed a fronto‐parietal network encompassing bilateral intraparietal sulcus (IPS), left pre‐supplementary motor area (PreSMA), left precentral gyrus (PreCG), and right dorsolateral prefrontal cortex (DLPFC). The network was driven by an intraparietal IPS‐IPS circuit hosting a representation of numerical quantity intertwined with a fronto‐parietal DLPFC‐IPS circuit engaged in temporary storage and updating of arithmetic operations. Both circuits received additional inputs from the PreCG and PreSMA playing more of a supportive role in mental calculation. The high AC group compared to the low AC group displayed a greater activation in the right IPS and based its calculation more on a feedback driven intraparietal IPS‐IPS circuit, whereas the low competence group more on a feedback driven fronto‐parietal DLPFC‐IPS circuit. This study provides first evidence that multivariate GCM is a sensitive approach to investigate effective connectivity of mental processes involved in mental calculation and to compare group level performances for different populations. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Age differences in prefontal recruitment during verbal working memory maintenance depend on memory load

Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies have revealed age-related under-activation, where older adults show less regional brain activation compared to younger adults, as well as age-related over-activation, where older adults show greater activation compared to younger adults. These differences have been found across multiple task domains, including verbal working memory (WM). Curiously, both under-activation and over-activation of dorsolateral prefrontal cortex (DLPFC) have been found for older adults in verbal WM tasks. Here, we use event-related fMRI to test the hypothesis that age-related differences in activation depend on memory load (the number of items that must be maintained). Our predictions about the recruitment of prefrontal executive processes are based on the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH; Reuter-Lorenz and Cappell, 2008). According to this hypothesis, more neural resources are engaged by older brains to accomplish computational goals completed with fewer resources by younger brains. Therefore, seniors are more likely than young adults to show over-activations at lower memory loads, and under-activations at higher memory loads. Consistent with these predictions, in right DLPFC, we observed age-related over-activation with lower memory loads despite equivalent performance accuracy across age groups. In contrast, with the highest memory load, older adults were significantly less accurate and showed less DLPFC activation compared to their younger counterparts. These results are considered in relation to previous reports of activation-performance relations using similar tasks, and are found to support the viability of CRUNCH as an account of age-related compensation and its potential costs.     

Aberrant intra and inter network resting state functional connectivity in thyrotoxicosis

Thyroid hormones epigenetically play an important role in the regularisation of neural networks and in neural differentiation during brain development. The present study aimed to explore the intra and inter network resting state functional connectivity changes underlying the neurobehavioural symptoms in thyrotoxicosis. To understand the pathophysiological changes, we investigated the correlation between functional connectivity and clinical and behavioural measures. Twenty‐eight freshly diagnosed thyrotoxicosis patients suffering with symptoms such as palpitation, loss of weight, trembling and heat intolerance from days to weeks and 28 healthy controls were recruited for the study. Thyrotoxicosis patients showed significantly decreased functional connectivity in sensorimotor network, fronto‐temporal network, default mode network, right fronto‐parietal network, left fronto‐parietal network and salience network. Inter network functional connectivity was significantly reduced between the basal ganglia network and sensorimotor network and increased between the salience network and fronto‐temporal network in thyrotoxicosis. Cognitive functions such as visual retention, recognition of objects, mental balance and performance on neuropsychological tests (ie, the Bender Gestalt test, Nahar‐Benson test and Mini Mental State Examination) also showed significant decline in thyrotoxicosis patients. The altered intrinsic resting state functional connectivity might underlie these cognitive deficits. The increased functional connectivity between the salience network and fronto‐temporal network suggests the recruitment of additional neuronal circuitry needed to compensate for the neuropathology in the primary neural network in thyrotoxicosis.     

Altered frontostriatal coupling in pre‐manifest Huntington’s disease: effects of increasing cognitive load

Background and purpose: Functional neuroimaging studies have suggested a dysfunction of prefrontal regions in clinically pre‐symptomatic individuals with the Huntington’s disease (HD) gene mutation (pre‐HD) during cognitive processing. The objective of this study was to test the impact of cognitive demand on prefrontal connectivity in pre‐HD individuals. Methods: Sixteen healthy controls and sixteen pre‐HD subjects were studied using functional MRI and a verbal working memory task with increasing cognitive load. Load‐dependent functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) was investigated by means of psychophysiological interactions. Results: In pre‐HD subjects, aberrant functional connectivity of the left DLPFC was found at high working memory load levels only. Compared with healthy controls, pre‐HD individuals exhibited lower connectivity strength in the left putamen, the right anterior cingulate and the left medial prefrontal cortex. Pre‐HD individuals close to the onset of motor symptoms additionally exhibited lower connectivity strength in the right putamen and the left superior frontal cortex. The connectivity strength in the left putamen was associated with several clinical measures including CAG repeat length, Unified Huntington's Disease Rating Scale motor score and predicted years to manifest symptom onset. Conclusion: These findings suggest that early prefrontal connectivity abnormalities in pre‐HD individuals are modulated by cognitive demand.     

Dynamic causal modeling of load‐dependent modulation of effective connectivity within the verbal working memory network

Neuroimaging studies have consistently shown that working memory (WM) tasks engage a distributed neural network that primarily includes the dorsolateral prefrontal cortex, the parietal cortex, and the anterior cingulate cortex. The current challenge is to provide a mechanistic account of the changes observed in regional activity. To achieve this, we characterized neuroplastic responses in effective connectivity between these regions at increasing WM loads using dynamic causal modeling of functional magnetic resonance imaging data obtained from healthy individuals during a verbal n‐back task. Our data demonstrate that increasing memory load was associated with (a) right‐hemisphere dominance, (b) increasing forward (i.e., posterior to anterior) effective connectivity within the WM network, and (c) reduction in individual variability in WM network architecture resulting in the right‐hemisphere forward model reaching an exceedance probability of 99% in the most demanding condition. Our results provide direct empirical support that task difficulty, in our case WM load, is a significant moderator of short‐term plasticity, complementing existing theories of task‐related reduction in variability in neural networks. Hum Brain Mapp 35:3025–3035, 2014. © 2013 Wiley Periodicals, Inc.     

Propofol disrupts functional interactions between sensory and high-order processing of auditory verbal memory

Current theories suggest that disrupting cortical information integration may account for the mechanism of general anesthesia in suppressing consciousness. Human cognitive operations take place in hierarchically structured neural organizations in the brain. The process of low-order neural representation of sensory stimuli becoming integrated in high-order cortices is also known as cognitive binding. Combining neuroimaging, cognitive neuroscience, and anesthetic manipulation, we examined how cognitive networks involved in auditory verbal memory are maintained in wakefulness, disrupted in propofol-induced deep sedation, and re-established in recovery. Inspired by the notion of cognitive binding, an functional magnetic resonance imaging-guided connectivity analysis was utilized to assess the integrity of functional interactions within and between different levels of the task-defined brain regions. Task-related responses persisted in the primary auditory cortex (PAC), but vanished in the inferior frontal gyrus (IFG) and premotor areas in deep sedation. For connectivity analysis, seed regions representing sensory and high-order processing of the memory task were identified in the PAC and IFG. Propofol disrupted connections from the PAC seed to the frontal regions and thalamus, but not the connections from the IFG seed to a set of widely distributed brain regions in the temporal, frontal, and parietal lobes (with exception of the PAC). These later regions have been implicated in mediating verbal comprehension and memory. These results suggest that propofol disrupts cognition by blocking the projection of sensory information to high-order processing networks and thus preventing information integration. Such findings contribute to our understanding of anesthetic mechanisms as related to information and integration in the brain.     

Right inferior frontal gyrus: An integrative hub in tonal bilinguals

Right hemispheric dominance in tonal bilingualism is still controversial. In this study, we investigated hemispheric dominance in 30 simultaneous Bai‐Mandarin tonal bilinguals and 28 Mandarin monolinguals using multimodal neuroimaging. Resting‐state functional connectivity (RSFC) analysis was first performed to reveal the changes of functional connections within the language‐related network. Voxel‐based morphology (VBM) and tract‐based spatial statistics (TBSS) analyses were then used to identify bilinguals' alterations in gray matter volume (GMV) and fractional anisotropy (FA) of white matter, respectively. RSFC analyses revealed significantly increased functional connections of the right pars‐orbital part of the inferior frontal gyrus (IFG) with right caudate, right pars‐opercular part of IFG, and left inferior temporal gyrus in Bai‐Mandarin bilinguals compared to monolinguals. VBM and TBSS analyses further identified significantly greater GMV in right pars‐triangular IFG and increased FA in right superior longitudinal fasciculus (SLF) in bilinguals than in monolinguals. Taken together, these results demonstrate the integrative role of the right IFG in tonal language processing of bilinguals. Our findings suggest that the intrinsic language network in simultaneous tonal bilinguals differs from that of monolinguals in terms of both function and structure.     

Partial support for ZNF804A genotype‐dependent alterations in prefrontal connectivity

Genome‐wide association studies identified the single nucleotide polymorphism rs1344706 in ZNF804A as a common risk‐variant for schizophrenia and bipolar disorder. Whereas the molecular function of ZNF804A is yet unclear, recent imaging genetics studies have started to characterize the neural systems architecture linking rs1344706 genotype to psychosis. Carring rs1344706 risk‐alleles was associated with a decrease in functional connectivity within the dorsolateral prefrontal cortices (DLPFCs) as well as an increase in connectivity between the DLPFC and the hippocampal formation (HF) in the context of a working memory task. The present study aimed at replicating these findings in an independent sample of 94 healthy subjects. Subjects were genotyped for rs1344706 and performed a working memory task during functional magnetic resonance imaging. Results indicate no support for a decrease of functional coupling between the bilateral DLPFCs at higher ZNF804A risk status. However, the current data show the previously described alteration in functional coupling between the right DLPFC and the HFs, albeit with weaker effects. Decoupled by default, the functional connectivity between the right DLPFC and anterior HFs increased with the number of rs1344706 risk alleles. The present data support fronto‐hippocampal dysconnectivity as intermediate phenotype linking rs1344706 genotype to psychosis. We discuss the issues in replicating the interhemispheric DLPFC coupling in light of the effect sizes rs1344706 genotype has on brain function, concluding that further independent replication studies are fundamentally needed to ascertain the role of rs1344706 in the functional integration of neural systems. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Disrupted functional connectivity for controlled visual processing as a basis for impaired spatial working memory in schizophrenia

Although regional brain abnormalities underlying spatial working memory (SWM) deficits in schizophrenia have been identified, little is known about which brain circuits are functionally disrupted in the SWM network in schizophrenia. We investigated SWM-related interregional functional connectivity in schizophrenia using functional magnetic resonance imaging (fMRI) data collected during a memory task that required analysis of spatial information in object structure. Twelve schizophrenia patients and 11 normal control subjects participated. Patients had SWM performance deficits and deficient neural activation in various brain areas, especially in the high SWM load condition. Examination of the covariation of regional brain activations elicited by the SWM task revealed evidence of functional disconnection between prefrontal and posterior visual association areas in schizophrenia. Under low SMW load, we found reduced functional associations between dorsolateral prefrontal cortex (DLPFC) and inferior temporal cortex (ITC) in the right hemisphere in patients. Under high SWM load, we found evidence for further functional disconnection in patients, including additional reduced functional associations between left DLPFC and right visual areas, including the posterior parietal cortex (PPC), fusiform gyrus, and V1, as well as between right inferior frontal cortex and right PPC. Greater prefrontal-posterior cortical functional connectivity was associated with better SWM performance in controls, but not in patients. These results suggest that prefrontal-posterior functional connectivity associated with the maintenance and control of visual information is central to SWM, and that disruption of this functional network underlies SWM deficits in schizophrenia.