Abnormalities of functional connectivity in the default mode network (DMN) recently have been reported in patients with amnestic mild cognitive impairment (aMCI), Alzheimer’s disease (AD) or other psychiatric diseases. As such, these abnormalities may be epiphenomena instead of playing a causal role in AD progression. To date, few studies have investigated specific brain networks, which extend beyond DMN involved in the early AD stages, especially in aMCI. The insula is one site affected by early pathological changes in AD and is a crucial hub of the human brain networks. Currently, we explored the contribution of the insula networks to cognitive performance in aMCI patients. Thirty aMCI and 26 cognitively normal (CN) subjects participated in this study. Intrinsic connectivity of the insula networks was measured, using the resting-state functional connectivity fMRI approach. We examined the differential connectivity of insula networks between groups, and the neural correlation between the altered insula networks connectivity and the cognitive performance in aMCI patients and CN subjects, respectively. Insula subregional volumes were also investigated. AMCI subjects, when compared to CN subjects, showed significantly reduced right posterior insula volumes, cognitive deficits and disrupted intrinsic connectivity of the insula networks. Specifically, decreased intrinsic connectivity was primarily located in the frontal-parietal network and the cingulo-opercular network, including the anterior prefrontal cortex (aPFC), anterior cingulate cortex, operculum, inferior parietal cortex and precuneus. Increased intrinsic connectivity was primarily situated in the visual-auditory pathway, which included the posterior superior temporal gyrus and middle occipital gyrus. Conjunction analysis was performed; and significantly decreased intrinsic connectivity in the overlapping regions of the anterior and posterior insula networks, including the bilateral aPFC, left dorsolateral prefrontal cortex, dorsomedial prefrontal cortex, and anterior temporal pole was found. Furthermore, the disrupted intrinsic connectivity was associated with episodic memory (EM) deficits in the aMCI patients and not in the CN subjects. These findings demonstrated that the functional integration of the insula networks plays an important role in the EM process. They provided new insight into the neural mechanism underlying the memory deficits in aMCI patients.

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Addiction is a chronic relapsing disorder hypothesized to be produced by drug-induced plasticity that renders individuals vulnerable to craving-inducing stimuli such as re-exposure to the drug of abuse. Drug-induced plasticity that may result in the addiction phenotype includes increased excitatory signaling within corticostriatal pathways which correlates with craving in humans and is necessary for reinstatement in rodents. Reduced cystine-glutamate exchange by system xc-appears to contribute to heightened excitatory signaling within the striatum, thereby posing this as a novel target in the treatment of addiction. In the present report, we examined the impact of repeated N-acetyl cysteine, which is commonly used to activate cystine-glutamate exchange, on reinstatement in rodents in a preclinical study and on craving in cocaine-dependent humans in a preliminary, proof of concept clinical experiment. Interestingly, repeated administration (seven days) of N-acetyl cysteine (60 mg/kg, IP) produced a significant reduction in cocaine- (10 mg/kg, IP) induced reinstatement, even though rats (N=10-12/group) were tested 24 hrs after the last administration of N-acetyl cysteine. The reduction in behavior despite the absence of the N-acetyl cysteine indicates that repeated N-acetyl cysteine may have altered drug-induced plasticity that underlies drug-seeking behavior. In parallel, our preliminary clinical data indicate that repeated administration (four days) of N-acetyl cysteine (1200-2400 mg/day) to cocaine-dependent human subjects (N=4/group) produced a significant reduction in craving following an experimenter-delivered IV injection of cocaine (20 mg/70 kg/60 sec). Collectively, these data demonstrate that N-acetyl cysteine diminishes the motivational qualities of a cocaine challenge injection possibly by altering pathogenic drug-induced plasticity.

The spatial relationship between a measured fMRI signal and its underlying neuronal activity remains unclear. One obstacle is the localization of neuronal activity; another is the spatial resolution of fMRI. In the present study, high-resolution BOLD and CBV fMRI experiments (voxel size: 156 ؋ 156 ؋ 2000 m 3 ) were conducted in the rat whisker barrel cortex at 3 T; neuronal activity across cortical layers was mapped using the Fos expression technique. Results show that BOLD response is weighted by blood volume and that pixels with high BOLD response can be located at the cortical surface or in deep layers, depending on local vasculature. In contrast to BOLD response, the pixels with high CBV response were consistently clustered in the deep cortical layers. Percentage-CBV change in cortical layers IV-V was 7.3 ؎ 1.5%, which was significantly higher than in layers I-III (4.1 ؎ 0.9%) and VI (4.3 ؎ 0.7%) (mean ؎ SEM). The laminar distribution of CBV response correlates well with neuronal activity localized by Fos expression. We conclude that neuronal activity can be inferred from CBV fMRI data with high spatial accuracy. The data indicate that both intracolumn functional connectivity and neurovascular coupling can be studied using CBV fMRI.

These findings suggest that l-THP is potentially useful for treating cocaine addiction.

Differentiation of absolute metabolite concentrations between gray and white matter in the occipital region of normal human brain was performed by in vivo localized single-voxel 1H magnetic resonance spectroscopy at 1.5 Tesla with long echo time (136 ms). With the combination of image segmentation between white and gray matter and cerebrospinal fluid, signal compensation of T1 and T2 effects, tissue water signal as the internal concentration reference, as well as compensation by different water contents in gray and white matters, it was determined that the levels of N-acetylaspartate (NAA), creatine and/or phosphocreatine (Cr), and choline-containing compounds (Cho) in gray matter were significantly higher than in white matter. The averaged NAA, Cr, and Cho concentrations in gray matter were 11.0, 9.7, and 1.9 mM/liter, respectively, in comparison with 7.5, 5.2, and 1.6 mM/liter in white matter. These results suggest that precise composition of white and gray matter and cerebrospinal fluid is necessary to avoid partial voluming effect in a single voxel and to accurately quantify the metabolite concentrations.

Acetylcholinesterase inhibitors (AChEIs), such as donepezil, have been shown to improve cognition in mild to moderate Alzheimer’s disease (AD) patients. In this paper, our goal is to determine the relationship between altered cerebral blood flow (CBF) and intrinsic functional network connectivity changes in mild AD patients before and after 12-week donepezil treatment. An integrative neuroimaging approach was employed by combining pseudocontinuous arterial spin labeling (pCASL) MRI and resting-state functional MRI (R-fMRI) methods to determine the changes in CBF and functional connectivity (FC) in the cholinergic pathway. Linear regression analyses determined the correlations of the regional CBF alterations and functional connectivity changes with cognitive responses. These were measured with the Mini-Mental Status Examination (MMSE) scores and Alzheimer’s disease Assessment Scale-Cognitive subscale (ADAS-cog) scores. Our results show that the regional CBF in mild AD subjects after donepezil treatment was significantly increased in the middle cingulate cortex (MCC) and posterior cingulate cortex (PCC), which are the neural substrates of the medial cholinergic pathway. In both brain regions, the baseline CBF and its changes after treatment were significantly correlated with the behavioral changes in ADAS-cog scores. The intrinsic FC was significantly enhanced in the medial cholinergic pathway network in the brain areas of the parahippocampal, temporal, parietal and prefrontal cortices. Finally, the FC changes in the medial prefrontal areas demonstrated an association with the CBF level in the MCC and the PCC, and also were correlated with ADAS-cog score changes. These findings indicate that regional CBF and FC network changes in the medial cholinergic pathway were associated with cognitive performance. It also is suggested that the combined pCASL-MRI and R-fMRI methods could be used to detect regional CBF and FC changes when using drug treatments in mild AD subjects.

Purpose To identify the neural correlates of cognitive improvement in mild AD subjects, following 12 weeks of donepezil treatment. Materials and Methods Resting-state functional connectivity MRI (R-fMRI) was used to measure the hippocampal functional connectivity (HFC) in 14 mild AD and 18 age-matched normal (CN) subjects. AD subjects were scanned at baseline and after donepezil treatment. CN subjects were scanned only at baseline as a reference to identify regions correlated or anticorrelated to the hippocampus. Before each scan, participants underwent cognitive, behavioral and functional assessments. Results After donepezil treatment, neural correlates of cognitive improvement measured by Mini-Mental State Examination scores were identified in the left parahippocampus, dorsolateral prefrontal cortex (DLPFC) and inferior frontal gyrus. Improvement in AD Assessment Scale-cognitive subscale scores correlated with the HFC changes in the left DLPFC and middle frontal gyrus. Stronger recovery in the network connectivity was associated with cognitive improvement. Conclusion R-fMRI may provide novel insight into the brain's functional responses to AD treatment in clinical pharmacological trials, and also may predict clinical response.