Association between Thalamocortical Functional Connectivity Abnormalities and Cognitive Deficits in Schizophrenia.

Cognitive deficits are considered a core component of schizophrenia and may predict functional outcome. However, the neural underpinnings of neuropsychological impairment remain to be fully elucidated. Data of 59 schizophrenia patients and 72 healthy controls from a public resting-state fMRI database was employed in our study. Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Battery was used to measure deficits of cognitive abilities in schizophrenia. Neural correlates of cognitive deficits in schizophrenia were examined by linear regression analysis of the thalamocortical network activity with scores of seven cognitive domains. We confirmed the combination of reduced prefrontal-thalamic connectivity and increased sensorimotor-thalamic connectivity in patients with schizophrenia. Correlation analysis with cognition revealed that in schizophrenia (1) the thalamic functional connectivity in the bilateral pre- and postcentral gyri was negatively correlated with attention/vigilance and speed of processing (Pearson's r ≤ -0.443, p ≤ 0.042, FWE corrected), and positively correlated with patients' negative symptoms (Pearson's r ≥ 0.375, p ≤ 0.003, FWE corrected); (2) the thalamic functional connectivity in the right cerebellum was positively correlated with speed of processing (Pearson's r = 0.388, p = 0.01, FWE corrected). Our study demonstrates that thalamic hyperconnectivity with sensorimotor areas is related to the severity of cognitive deficits and clinical symptoms, and extends our understanding of the neural underpinnings of "cognitive dysmetria" in schizophrenia.

The antipsychotic drug quetiapine stimulates oligodendrocyte differentiation by modulating the cell cycle.

Recent studies have revealed that oligodendrocyte differentiation deficits and de-myelination occur in the brains of schizophrenic patients. Cell cycle proteins play a critical role in modulating oligodendrocyte proliferation and differentiation. In our previous studies, we found that cuprizone, a copper chelant, induces oligodendrocyte loss and demyelination, and this effect can be alleviated by using the atypical antipsychotic drug quetiapine. To explore the mechanisms of quetiapine in oligodendrocyte development, we examined the effects of quetiapine on cell cycle progression. Quetiapine promoted cell cycle exit and blocked the mitogenic effect of PDGF in cultured rat cortical oligodendrocyte progenitor cells (OPCs). Quetiapine accelerated OPC differentiation in vitro. Moreover, the systemic administration of quetiapine up-regulated p21 mRNA expression, a cyclin-dependent kinase inhibitor, in mice. Knocking down p21 expression by RNA interference enhanced proliferation and delayed differentiation. Our results suggest that cell cycle regulation may contribute to the differentiation-promoting effect of quetiapine.

Impact of aberrant cerebral perfusion on resting-state functional MRI: A preliminary investigation of Moyamoya disease.

The impact of chronic cerebral hypoperfusion on resting-state blood oxygen level-dependent signal fluctuations remains unknown. We aimed to determine whether chronic ischemia induces changes in amplitude of low-frequency fluctuations (ALFF) and to investigate the correlation between ALFF and perfusion-weighted magnetic resonance imaging (PWI) parameters in patients with moyamoya disease (MMD). Thirty patients with pre- and postoperative resting-state functional magnetic resonance imaging and PWI were included, and thirty normal controls underwent resting-state functional magnetic resonance imaging. A decrease in preoperative frontal lobe ALFF was observed in patients with MMD. Postoperative frontal lobe ALFF showed moderate improvement but still remained lower than those in normal controls. The values of mean transit time and time-to-peak, but not cerebral blood volume and cerebral blood flow, correlated significantly with frontal lobe ALFF. Moreover, there were significant negative correlations between changes in frontal lobe PWI parameters and changes in frontal lobe ALFF on both operated side and contralateral side after the unilateral revascularization surgery. Our results demonstrate that reduced ALFF are closely related to the abnormal PWI parameters and vary with the alteration of cerebral perfusion in patients with MMD.

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model.

The cuprizone (CPZ) model has been widely used for the studies of de-and remyelination. The CPZ-exposed mice show oligodendrocyte precursor cells (OPCs) increase and mature oligodendrocytes decrease, suggesting an imbalance between proliferation and differentiation of OPCs. In the first experiment of this study, we examined the expression of cell cycle related genes in brains of mice following CPZ administration for 5 weeks by means of microarray assay. In addition, we performed a double labeling of BrdU and Ki-67 to calculate cell cycle exit index in the mice. Our results showed that CPZ administration up-regulated the expression of 16 cell cycle related genes, but down-regulated the expression of only one in the prefrontal cortex (PFC) of mice compared to control group. The treatment inhibited potential precursor cells exit from cell cycle. In the second experiment, we evaluated effects of a CDK inhibitor flavopiridol (FLA) on CPZ-induced neuropathological changes and spatial working memory impairment in mice.FLA treatment for one week effectively attenuated the CPZ-induced increases in NG2 positive cells, microglia and astrocytes, alleviated the concurrent mature oligodendrocyte loss and myelin breakdown, and improved spatial working memory deficit in the CPZ-exposed mice. These results suggest that CPZ-induced neuropathological changes involve in dysregulation of cell cycle related genes. The therapeutic effects of FLA on CPZ-exposed mice may be related to its ability of cell cycle inhibition.

l-Scoulerine attenuates behavioural changes induced by methamphetamine in zebrafish and mice.

Methamphetamine (METH), a substance with a high potential for abuse and addiction, is a serious worldwide public health problem. METH addicts often show extreme paranoia, anxiety, and depression. Thus, there is no effective medication for the treatment of METH-induced abnormalities. In the present study, we investigated the effects of l-Scoulerine (l-SLR), a tetrahydroprotoberberine (THPBS) alkaloid, on METH-induced anxiety-like behaviour in zebrafish and METH-induced addictive behavior in mice. In the novel tank test, acute administration of METH (2 mg/L) induced a significant decrease in the number of total vertical transitions and time spent in the upper zone. Moreover, METH produced significant avoidance behaviour showing increased swimming time in the central area and high speed movement in the mirror area in the mirror stimulation test; these anxiety-like changes were attenuated by l-SLR. Chronic administration of METH (2 mg/kg) produced a steady increase in locomotor activity and conditioned place preference in mice. l-SLR (5 mg/kg) failed to reduce acute METH-induced hyperlocomotion, but attenuated chronic METH-induced behavioural sensitization and significantly blocked the expression of conditioned place preference induced by METH in mice. The present study suggests that l-SLR may be a promising agent for the treatment of addiction and anxiety induced by METH.

Abnormal gray matter volume and resting-state functional connectivity in former heroin-dependent individuals abstinent for multiple years.

Previous studies have suggested that heroin addiction is associated with structural and functional brain abnormalities. However, it is largely unknown whether these characteristics of brain abnormalities would be persistent or restored after long periods of abstinence. Considering the very high rates of relapse, we hypothesized that there may exist some latent neural vulnerabilities in abstinent heroin users. In this study, structural and resting-state functional magnetic resonance imaging data were collected from 30 former heroin-dependent (FHD) subjects who were drug free for more than 3 years and 30 non-addicted control (CN) volunteers. Voxel-based morphometry was used to identify possible gray matter volume differences between the FHD and CN groups. Alterations in resting-state functional connectivity in FHD were examined using brain areas with gray matter deficits as seed regions. Significantly reduced gray matter volume was observed in FHD in an area surrounding the parieto-occipital sulcus, which included the precuneus and cuneus. Functional connectivity analyses revealed that the FHD subjects showed reduced positive correlation within the default mode network and visual network and decreased negative correlation between the default mode network, visual network and task positive network. Moreover, the altered functional connectivity was correlated with self-reported impulsivity scores in the FHD subjects. Our findings suggest that disruption of large-scale brain systems is present in former heroin users even after multi-year abstinence, which could serve as system-level neural underpinnings for behavioral dysfunctions associated with addiction.

Recovery Sleep Reverses Impaired Response Inhibition due to Sleep Restriction: Evidence from a Visual Event Related Potentials Study.

OBJECTIVE: To investigate response inhibition after total sleep deprivation (TSD) and the restorative effects of one night of recovery sleep (RS). METHODS: Fourteen healthy male participants performed a visual Go/NoGo task, and electroencephalogram recordings were conducted at five time points: (1) baseline, (2) after 12 h of TSD, (3) after 24 h of TSD, (4) after 36 h of TSD, and (5) following 8 h of RS. The dynamic changes in response inhibition during TSD and after 8 h of RS were investigated by examining the NoGo-N2 and NoGo-P3 event-related potential components. RESULTS: Compared with baseline, NoGo-P3 amplitudes were decreased, while the NoGo-N2 latency increased along with the awake time prolonged. NoGo anteriorization, which was minimized after 24 h of TSD, progressively decreased with increasing TSD. After 8 h of RS, recoveries of both the NoGo-P3 amplitude and NoGo-N2 latency in the prefrontal cortex were observed compared with the values after 36 h of TSD. CONCLUSION: TSD induced a dose-dependent functional decline in the response inhibition of NoGo-N2 and NoGo-P3 on prefrontal cortex activation, and 8 h of RS resulted in recovery or maintenance of the response inhibition. However, it was not restored to baseline levels. LIMITATIONS: Participants were chosen male college students only, thus the findings cannot be generalized to older people and women. Additionally, the sample size was small, and, thus, speculations on the meaning of the results of this study should be cautious. The EEG continuous recording should be employed to monitor the decline of alertness following TSD.

Altered superficial amygdala-cortical functional link in resting state after 36 hours of total sleep deprivation.

The superficial amygdala (SFA) is important in human emotion/affective processing via its strong connection with other limbic and cerebral cortex for receptive and expressive emotion processing. Few studies have investigated the functional connectivity changes of the SFA under extreme conditions, such as prolonged sleep loss, although the SFA showed a distinct functional connectivity pattern throughout the brain. In this study, resting-state functional magnetic resonance imaging (rs-fMRI) was employed to investigate the changes of SFA-cortical functional connectivity after 36 hr of total sleep deprivation (TSD). Fourteen healthy male volunteers aged 25.9 ± 2.3 years (range 18-28 years) enrolled in this within-subject crossover study. We found that the right SFA showed increased functional connectivity with the right medial prefrontal cortex (mPFC) and decreased functional connectivity with the right dorsal posterior cingulate cortex (dPCC) in the resting brain after TSD compared with that during rested wakefulness. For the left SFA, decreased connectivity with the right dorsal anterior cingulate cortex (dACC) and right dPCC was found. Further regression analysis indicated that the functional link between mPFC and SFA significantly correlated with the Profile of Mood State scores. Our results suggest that the amygdala cannot be treated as a single unit in human neuroimaging studies and that TSD may alter the functional connectivity pattern of the SFA, which in turn disrupts emotional regulation.

Large-Scale Brain Network Coupling Predicts Total Sleep Deprivation Effects on Cognitive Capacity.

Interactions between large-scale brain networks have received most attention in the study of cognitive dysfunction of human brain. In this paper, we aimed to test the hypothesis that the coupling strength of large-scale brain networks will reflect the pressure for sleep and will predict cognitive performance, referred to as sleep pressure index (SPI). Fourteen healthy subjects underwent this within-subject functional magnetic resonance imaging (fMRI) study during rested wakefulness (RW) and after 36 h of total sleep deprivation (TSD). Self-reported scores of sleepiness were higher for TSD than for RW. A subsequent working memory (WM) task showed that WM performance was lower after 36 h of TSD. Moreover, SPI was developed based on the coupling strength of salience network (SN) and default mode network (DMN). Significant increase of SPI was observed after 36 h of TSD, suggesting stronger pressure for sleep. In addition, SPI was significantly correlated with both the visual analogue scale score of sleepiness and the WM performance. These results showed that alterations in SN-DMN coupling might be critical in cognitive alterations that underlie the lapse after TSD. Further studies may validate the SPI as a potential clinical biomarker to assess the impact of sleep deprivation.

Nature of functional links in valuation networks differentiates impulsive behaviors between abstinent heroin-dependent subjects and nondrug-using subjects.

Advanced neuroimaging studies have identified brain correlates of pathological impulsivity in a variety of neuropsychiatric disorders. However, whether and how these spatially separate and functionally integrated neural correlates collectively contribute to aberrant impulsive behaviors remains unclear. Building on recent progress in neuroeconomics toward determining a biological account of human behaviors, we employed resting-state functional MRI to characterize the nature of the links between these neural correlates and to investigate their impact on impulsivity. We demonstrated that through functional connectivity with the ventral medial prefrontal cortex, the δ-network (regions of the executive control system, such as the dorsolateral prefrontal cortex) and the ß-network (regions of the reward system involved in the mesocorticolimbic pathway), jointly influence impulsivity measured by the Barratt impulsiveness scale scores. In control nondrug-using subjects, the functional link between the ß- and δ-networks is balanced, and the δ-network competitively controls impulsivity. However, in abstinent heroin-dependent subjects, the link is imbalanced, with stronger ß-network connectivity and weaker δ-network connectivity. The imbalanced link is associated with impulsivity, indicating that the ß- and δ-networks may mutually reinforce each other in abstinent heroin-dependent subjects. These findings of an aberrant link between the ß- and δ-networks in abstinent heroin-dependent subjects may shed light on the mechanism of aberrant behaviors of drug addiction and may serve as an endophenotype to mark individual subjects' self-control capacity.

Disruptive changes of cerebellar functional connectivity with the default mode network in schizophrenia.

The default mode network (DMN) plays an important role in the physiopathology of schizophrenia. Previous studies have suggested that the cerebellum participates in higher-order cognitive networks such as the DMN. However, the specific contribution of the cerebellum to the DMN abnormalities in schizophrenia has yet to be established. In this study, we investigated cerebellar functional connectivity differences between 60 patients with schizophrenia and 60 healthy controls from a public resting-state fMRI database. Seed-based correlation analysis was performed by using seeds from the left Crus I, right Crus I and Lobule IX, which have previously been identified as being involved in the DMN. Our results revealed that, compared with the healthy controls, the patients showed significantly reduced cerebellar functional connectivity with the thalamus and several frontal regions including the middle frontal gyrus, anterior cingulate cortex, and supplementary motor area. Moreover, the positive correlations between the strength of frontocerebellar and thalamocerebellar functional connectivity observed in the healthy subjects were diminished in the patients. Our findings implicate disruptive changes of the fronto-thalamo-cerebellar circuit in schizophrenia, which may provide further evidence for the "cognitive dysmetria" concept of schizophrenia.

Altered resting-state amygdala functional connectivity after 36 hours of total sleep deprivation.

OBJECTIVES: Recent neuroimaging studies have identified a potentially critical role of the amygdala in disrupted emotion neurocircuitry in individuals after total sleep deprivation (TSD). However, connectivity between the amygdala and cerebral cortex due to TSD remains to be elucidated. In this study, we used resting-state functional MRI (fMRI) to investigate the functional connectivity changes of the basolateral amygdala (BLA) and centromedial amygdala (CMA) in the brain after 36 h of TSD. MATERIALS AND METHODS: Fourteen healthy adult men aged 25.9 ± 2.3 years (range, 18-28 years) were enrolled in a within-subject crossover study. Using the BLA and CMA as separate seed regions, we examined resting-state functional connectivity with fMRI during rested wakefulness (RW) and after 36 h of TSD. RESULTS: TSD resulted in a significant decrease in the functional connectivity between the BLA and several executive control regions (left dorsolateral prefrontal cortex [DLPFC], right dorsal anterior cingulate cortex [ACC], right inferior frontal gyrus [IFG]). Increased functional connectivity was found between the BLA and areas including the left posterior cingulate cortex/precuneus (PCC/PrCu) and right parahippocampal gyrus. With regard to CMA, increased functional connectivity was observed with the rostral anterior cingulate cortex (rACC) and right precentral gyrus. CONCLUSION: These findings demonstrate that disturbance in amygdala related circuits may contribute to TSD psychophysiology and suggest that functional connectivity studies of the amygdala during the resting state may be used to discern aberrant patterns of coupling within these circuits after TSD.

Altered intrinsic hippocmapus declarative memory network and its association with impulsivity in abstinent heroin dependent subjects.

Converging evidence suggests that addiction can be considered a disease of aberrant learning and memory with impulsive decision-making. In the past decades, numerous studies have demonstrated that drug addiction is involved in multiple memory systems such as classical conditioned drug memory, instrumental learning memory and the habitual learning memory. However, most of these studies have focused on the contributions of non-declarative memory, and declarative memory has largely been neglected in the research of addiction. Based on a recent finding that hippocampus, as a core functioning region of declarative memory, was proved biased the decision-making process based on past experiences by spreading associated reward values throughout memory. Our present study focused on the hippocampus. By utilizing seed-based network analysis on the resting-state functional MRI datasets with the seed hippocampus we tested how the intrinsic hippocampal memory network altered toward drug addiction, and examined how the functional connectivity strength within the altered hippocampal network correlated with behavioral index 'impulsivity'. Our results demonstrated that HD group showed enhanced coherence between hippocampus which represents declarative memory system and non-declarative reward-guided learning memory system, and also showed attenuated intrinsic functional link between hippocampus and top-down control system, compared to the CN group. This alteration was furthered found to have behavioral significance over the behavioral index 'impulsivity' measured with Barratt Impulsiveness Scale (BIS). These results provide insights into the mechanism of declarative memory underlying the impulsive behavior in drug addiction.

Decreased thalamocortical functional connectivity after 36 hours of total sleep deprivation: evidence from resting state FMRI.

OBJECTIVES: The thalamus and cerebral cortex are connected via topographically organized, reciprocal connections, which hold a key function in segregating internally and externally directed awareness information. Previous task-related studies have revealed altered activities of the thalamus after total sleep deprivation (TSD). However, it is still unclear how TSD impacts on the communication between the thalamus and cerebral cortex. In this study, we examined changes of thalamocortical functional connectivity after 36 hours of total sleep deprivation by using resting state function MRI (fMRI). MATERIALS AND METHODS: Fourteen healthy volunteers were recruited and performed fMRI scans before and after 36 hours of TSD. Seed-based functional connectivity analysis was employed and differences of thalamocortical functional connectivity were tested between the rested wakefulness (RW) and TSD conditions. RESULTS: We found that the right thalamus showed decreased functional connectivity with the right parahippocampal gyrus, right middle temporal gyrus and right superior frontal gyrus in the resting brain after TSD when compared with that after normal sleep. As to the left thalamus, decreased connectivity was found with the right medial frontal gyrus, bilateral middle temporal gyri and left superior frontal gyrus. CONCLUSION: These findings suggest disruptive changes of the thalamocortical functional connectivity after TSD, which may lead to the decline of the arousal level and information integration, and subsequently, influence the human cognitive functions.

Identification of hyperactive intrinsic amygdala network connectivity associated with impulsivity in abstinent heroin addicts.

Impulsivity is a pathological hallmark of drug addiction. However, little is known about the neuropsychological underpinnings of this impaired impulsive control network on drug addiction. Twenty two abstinent heroin dependent (HD) subjects and 15 cognitively normal (CN) subjects participated in this study. Resting-state functional connectivity MRI was employed to measure abnormalities in the intrinsic amygdala functional connectivity (iAFC) network activity and the Barratt Impulsive Scale, 11th version was used to measure impulsivity. Linear regression analysis was applied to detect the neural constructs underlying impulsivity by correlating iAFC network activity with impulsive scores. In the HD group, higher impulsivity scores and significantly enhanced iAFC network activity were found, especially in bilateral thalamus, right insula, and inferior frontal gyrus. Markedly decreased anticorrelated iAFC network activity was seen in the left precuneus, and even switched to positive correlation pattern in right precuneus, relative to the CN group. The iAFC network strengths in the HD group were positively correlated with impulsivity in the right subcallosal gyrus, insula, thalamus and posterior cingulate cortex, and negatively correlated in left fusiform area. In the CN group, the left pre-somamotor area-amygdala connectivity was positively correlated, and right orbital frontal cortex-amygdala and precuneus-amygdala connectivity were negatively correlated with impulsivity scores. Our study demonstrates different constructs of the impulsive network in HD and CN subjects. Altered iAFC network connectivity in HD subjects may contribute to the loss of impulsive control. This further facilitates our understanding of the neural underpinnings of behavior dysfunction in addiction.

Impaired response inhibition function in abstinent heroin dependents: an fMRI study.

Heroin, like various illicit substances, has a negative impact on the frontal cognitive function after repeated abuse. We used functional magnetic resonance imaging (fMRI) to examine the neural substrates of response inhibition and competition in 18 healthy controls and assess the frontal neurocognition in 30 abstinent heroin dependents (AHD) as they performed a Go/NoGo Association task with reaction times recorded spontaneously. The neural response which was induced by response inhibition was prominent in the midline structure, specifically the bilateral medial prefrontal gyrus and anterior cingulated cortex, as well as the left middle frontal gyrus, insula, bilateral inferior frontal gyrus and limbic system. Unlike drug-naïve controls, only the bilateral superior frontal gyrus and left middle frontal gyrus were activated in AHD. Furthermore, the RT of AHD was significantly longer than that of controls. The results suggest that: (1) the ACC, mPFC and inferior frontal lobe play an important role in response inhibition and competition; (2) heroin dependents had an impaired response inhibition function that lasted even months into abstinence, which indicates that the negative effect of heroin on the inhibitory function still continues in early protracted withdrawal state.