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1.  Microstructural White Matter Changes, Not Hippocampal Atrophy, Detect Early Amnestic Mild Cognitive Impairment 
PLoS ONE  2013;8(3):e58887.
Background
Alzheimer’s disease (AD) is generally considered to be characterized by pathology in gray matter of the brain, but convergent evidence suggests that white matter degradation also plays a vital role in its pathogenesis. The evolution of white matter deterioration and its relationship with gray matter atrophy remains elusive in amnestic mild cognitive impairment (aMCI), a prodromal stage of AD.
Methods
We studied 155 cognitively normal (CN) and 27 ‘late’ aMCI individuals with stable diagnosis over 2 years, and 39 ‘early’ aMCI individuals who had converted from CN to aMCI at 2-year follow up. Diffusion tensor imaging (DTI) tractography was used to reconstruct six white matter tracts three limbic tracts critical for episodic memory function - the fornix, the parahippocampal cingulum, and the uncinate fasciculus; two cortico-cortical association fiber tracts - superior longitudinal fasciculus and inferior longitudinal fasciculus; and one projection fiber tract - corticospinal tract. Microstructural integrity as measured by fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) was assessed for these tracts.
Results
Compared with CN, late aMCI had lower white matter integrity in the fornix, the parahippocampal cingulum, and the uncinate fasciculus, while early aMCI showed white matter damage in the fornix. In addition, fornical measures were correlated with hippocampal atrophy in late aMCI, whereas abnormality of the fornix in early aMCI occurred in the absence of hippocampal atrophy and did not correlate with hippocampal volumes.
Conclusions
Limbic white matter tracts are preferentially affected in the early stages of cognitive dysfunction. Microstructural degradation of the fornix preceding hippocampal atrophy may serve as a novel imaging marker for aMCI at an early stage.
doi:10.1371/journal.pone.0058887
PMCID: PMC3597581
2.  Chinese Specific Characteristics of Sporadic Creutzfeldt-Jakob Disease: A Retrospective Analysis of 57 Cases 
PLoS ONE  2013;8(3):e58442.
Objective
Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal and transmissible neurodegenerative disorder. However, no studies have reported Chinese specific characteristics of sCJD. We aimed to identify differences in sCJD between Chinese patients and patients from other countries.
Methods
The data from 57 Chinese sCJD patients were retrospectively analyzed, including demographic data, clinical manifestations, laboratory examinations, electroencephalograms (EEGs), diffusion-weighted imaging (DWI) scans, positron emission tomography (PET) scans, and pathological results.
Result
The disease was pathologically confirmed in 11 patients. 39 cases were diagnosed as probable sCJD, and 7 were possible. Of the total cases, 33 were male, and 24 were female. The onset age ranged from 36 to 75 years (mean: 55.5, median: 57). Disease onset before the age of 60 occurred in 57.9% of patients. The disease duration from onset to death ranged 5–22 months (mean: 11.6, median: 11), and 51.9% of patients died 7 to 12 months after disease onset. The majority of patients presented with sub-acute onset with progressive dementia. 3 of the 9 patients who took 14-3-3 protein analysis had positive results (33.3%). The sensitivity of EEG was 79.6% (43/54). For DWI and PET examinations, the sensitivities were 94% (47/50) and 94.1% (16/17), respectively. In seven patients who did not show typical hyper-intensities on the first DWI examination, abnormalities of hypo-metabolism in the cerebral cortex were clearly detected by PET. In 13 out of the 17 patients, PET detected extra abnormal regions in addition to the hyper-intense areas observed in DWI.
Conclusion
This is the first study to indicate that Chinese sCJD patients have a much earlier onset age and a longer disease duration than other populations, which is most likely related to racial differences. The longer disease duration may also be a probable characteristic of Asian populations. PET had high sensitivity for the diagnosis of sCJD.
doi:10.1371/journal.pone.0058442
PMCID: PMC3597718
3.  Regional Variation in Brain White Matter Diffusion Index Changes following Chemoradiotherapy: A Prospective Study Using Tract-Based Spatial Statistics 
PLoS ONE  2013;8(3):e57768.
Purpose
There is little known about how brain white matter structures differ in their response to radiation, which may have implications for radiation-induced neurocognitive impairment. We used diffusion tensor imaging (DTI) to examine regional variation in white matter changes following chemoradiotherapy.
Methods
Fourteen patients receiving two or three weeks of whole-brain radiation therapy (RT) ± chemotherapy underwent DTI pre-RT, at end-RT, and one month post-RT. Three diffusion indices were measured: fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). We determined significant individual voxel changes of diffusion indices using tract-based spatial statistics, and mean changes of the indices within fourteen white matter structures of interest.
Results
Voxels of significant FA decreases and RD increases were seen in all structures (p<0.05), with the largest changes (20–50%) in the fornix, cingula, and corpus callosum. There were highly significant between-structure differences in pre-RT to end-RT mean FA changes (p<0.001). The inferior cingula had a mean FA decrease from pre-RT to end-RT significantly greater than 11 of the 13 other structures (p<0.00385).
Conclusions
Brain white matter structures varied greatly in their response to chemoradiotherapy as measured by DTI changes. Changes in FA and RD related to white matter demyelination were prominent in the cingula and fornix, structures relevant to radiation-induced neurocognitive impairment. Future research should evaluate DTI as a predictive biomarker of brain chemoradiotherapy adverse effects.
doi:10.1371/journal.pone.0057768
PMCID: PMC3587621  PMID: 23469234
4.  Thermometry of Red Blood Cell Concentrate: Magnetic Resonance Decoding Warm Up Process 
PLoS ONE  2013;8(2):e57931.
Purpose
Temperature is a key measure in human red blood cell concentrate (RBC) quality control. A precise description of transient temperature distributions in RBC units removed from steady storage exposed to ambient temperature is at present unknown. Magnetic resonance thermometry was employed to visualize and analyse RBC warm up processes, to describe time courses of RBC mean, surface and core temperatures by an analytical model, and to determine and investigate corresponding model parameters.
Methods
Warm-up processes of 47 RBC units stored at 1–6°C and exposed to 21.25°C ambient temperature were investigated by proton resonance frequency thermometry. Temperature distributions were visualized and analysed with dedicated software allowing derivation of RBC mean, surface and core temperature-time courses during warm up. Time-dependence of mean temperature was assumed to fulfil a lumped capacitive model of heat transfer. Time courses of relative surface and core temperature changes to ambient temperature were similarly assumed to follow shifted exponential decays characterized by a time constant and a relative time shift, respectively.
Results
The lumped capacitive model of heat transfer and shifted exponential decays described time-dependence of mean, surface and core temperatures close to perfect (mean R2 were 0.999±0.001, 0.996±0.004 and 0.998±0.002, respectively). Mean time constants were τmean = 55.3±3.7 min, τsurface = 41.4±2.9 min and τcore = 76.8±7.1 min, mean relative time shifts were Δsurface = 0.07±0.02 and Δcore = 0.04±0.01. None of the constants correlated significantly with temperature differences between ambient and storage temperature.
Conclusion
Lumped capacitive model of heat transfer and shifted exponential decays represent simple analytical formulas to describe transient mean, surface and core temperatures of RBC during warm up, which might be a helpful tool in RBC temperature monitoring and quality control. Independence of constants on differences between ambient and storage temperature suggests validity of models for arbitrary storage and ambient temperatures.
doi:10.1371/journal.pone.0057931
PMCID: PMC3585280  PMID: 23469108
5.  MRI Evidence for Altered Venous Drainage and Intracranial Compliance in Mild Traumatic Brain Injury 
PLoS ONE  2013;8(2):e55447.
Purpose
To compare venous drainage patterns and associated intracranial hydrodynamics between subjects who experienced mild traumatic brain injury (mTBI) and age- and gender-matched controls.
Methods
Thirty adult subjects (15 with mTBI and 15 age- and gender-matched controls) were investigated using a 3T MR scanner. Time since trauma was 0.5 to 29 years (mean 11.4 years). A 2D-time-of-flight MR-venography of the upper neck was performed to visualize the cervical venous vasculature. Cerebral venous drainage through primary and secondary channels, and intracranial compliance index and pressure were derived using cine-phase contrast imaging of the cerebral arterial inflow, venous outflow, and the craniospinal CSF flow. The intracranial compliance index is the defined as the ratio of maximal intracranial volume and pressure changes during the cardiac cycle. MR estimated ICP was then obtained through the inverse relationship between compliance and ICP.
Results
Compared to the controls, subjects with mTBI demonstrated a significantly smaller percentage of venous outflow through internal jugular veins (60.9±21% vs. controls: 76.8±10%; p = 0.01) compensated by an increased drainage through secondary veins (12.3±10.9% vs. 5.5±3.3%; p<0.03). Mean intracranial compliance index was significantly lower in the mTBI cohort (5.8±1.4 vs. controls 8.4±1.9; p<0.0007). Consequently, MR estimate of intracranial pressure was significantly higher in the mTBI cohort (12.5±2.9 mmHg vs. 8.8±2.0 mmHg; p<0.0007).
Conclusions
mTBI is associated with increased venous drainage through secondary pathways. This reflects higher outflow impedance, which may explain the finding of reduced intracranial compliance. These results suggest that hemodynamic and hydrodynamic changes following mTBI persist even in the absence of clinical symptoms and abnormal findings in conventional MR imaging.
doi:10.1371/journal.pone.0055447
PMCID: PMC3566196  PMID: 23405151
6.  Preoperative Diffusion-Weighted Imaging of Single Brain Metastases Correlates with Patient Survival Times 
PLoS ONE  2013;8(2):e55464.
Background
MRI-based diffusion-weighted imaging (DWI) visualizes the local differences in water diffusion in vivo. The prognostic value of DWI signal intensities on the source images and apparent diffusion coefficient (ADC) maps respectively has not yet been studied in brain metastases (BM).
Methods
We included into this retrospective analysis all patients operated for single BM at our institution between 2002 and 2010, in whom presurgical DWI and BM tissue samples were available. We recorded relevant clinical data, assessed DWI signal intensity and apparent diffusion coefficient (ADC) values and performed histopathological analysis of BM tissues. Statistical analyses including uni- and multivariate survival analyses were performed.
Results
65 patients (34 female, 31 male) with a median overall survival time (OS) of 15 months (range 0–99 months) were available for this study. 19 (29.2%) patients presented with hyper-, 3 (4.6%) with iso-, and 43 (66.2%) with hypointense DWI. ADCmean values could be determined in 32 (49.2%) patients, ranged from 456.4 to 1691.8*10−6 mm2/s (median 969.5) and showed a highly significant correlation with DWI signal intensity. DWI hyperintensity correlated significantly with high amount of interstitial reticulin deposition. In univariate analysis, patients with hyperintense DWI (5 months) and low ADCmean values (7 months) had significantly worse OS than patients with iso/hypointense DWI (16 months) and high ADCmean values (30 months), respectively. In multivariate survival analysis, high ADCmean values retained independent statistical significance.
Conclusions
Preoperative DWI findings strongly and independently correlate with OS in patients operated for single BM and are related to interstitial fibrosis. Inclusion of DWI parameters into established risk stratification scores for BM patients should be considered.
doi:10.1371/journal.pone.0055464
PMCID: PMC3564927  PMID: 23393579
7.  Motor Training Increases the Stability of Activation Patterns in the Primary Motor Cortex 
PLoS ONE  2013;8(1):e53555.
Learning to be skillful is an endowed talent of humans, but neural mechanisms underlying behavioral improvement remain largely unknown. Some studies have reported that the mean magnitude of neural activation is increased after learning, whereas others have instead shown decreased activation. In this study, we used functional magnetic resonance imaging (fMRI) to investigate learning-induced changes in the neural activation in the human brain with a classic motor training task. Specifically, instead of comparing the mean magnitudes of activation before and after training, we analyzed the learning-induced changes in multi-voxel spatial patterns of neural activation. We observed that the stability of the activation patterns, or the similarity of the activation patterns between the even and odd runs of the fMRI scans, was significantly increased in the primary motor cortex (M1) after training. By contrast, the mean magnitude of neural activation remained unchanged. Therefore, our study suggests that learning shapes the brain by increasing the stability of the activation patterns, therefore providing a new perspective in understanding the neural mechanisms underlying learning.
doi:10.1371/journal.pone.0053555
PMCID: PMC3538534  PMID: 23308252
8.  Fast Diffusion Tensor Magnetic Resonance Imaging of the Mouse Brain at Ultrahigh-Field: Aiming at Cohort Studies 
PLoS ONE  2012;7(12):e53389.
Introduction
In-vivo high resolution diffusion tensor imaging (DTI) of the mouse brain is often limited by the low signal to noise ratio (SNR) resulting from the required small voxel sizes. Recently, cryogenically cooled resonators (CCR) have demonstrated significant increase of the effective SNR. It is the objective of this study to enable fast DTI of the mouse brain. In this context, CCRs appear attractive for SNR improvement.
Methods
Three mice underwent a DTI examination at 1562×250 µm3 spatial resolution with a CCR at ultrahigh field (11.7T). Diffusion images were acquired along 30 gradient directions plus 5 references without diffusion encoding, resulting in a total acquisition time of 35 minutes. For comparison, mice additionally underwent a standardized 110 minutes acquisition protocol published earlier. Fractional anisotropy (FA) and fiber tracking (FT) results including quantitative tractwise fractional anisotropy statistics (TFAS) were qualitatively and quantitatively compared.
Results
Qualitative and quantitative assessment of the calculated fractional anisotropy maps and fibre tracking results showed coinciding outcome comparing 35 minute scans to the standardized 110 minute scan. Coefficients of variation for ROI-based FA-comparison as well as for TFAS revealed comparable results for the different scanning protocols.
Conclusion
Mouse DTI at 11.7 T was performed with an acquisition time of approximately 30 minutes, which is considered feasible for cohort studies. The rapid acquisition protocol reveals reliable and reproducible FA-values and FT reconstructions, thus allowing an experimental setup for in-vivo large scale whole brain murine DTI cohort studies.
doi:10.1371/journal.pone.0053389
PMCID: PMC3532447  PMID: 23285289
9.  Anatomical Brain Images Alone Can Accurately Diagnose Chronic Neuropsychiatric Illnesses 
PLoS ONE  2012;7(12):e50698.
Objective
Diagnoses using imaging-based measures alone offer the hope of improving the accuracy of clinical diagnosis, thereby reducing the costs associated with incorrect treatments. Previous attempts to use brain imaging for diagnosis, however, have had only limited success in diagnosing patients who are independent of the samples used to derive the diagnostic algorithms. We aimed to develop a classification algorithm that can accurately diagnose chronic, well-characterized neuropsychiatric illness in single individuals, given the availability of sufficiently precise delineations of brain regions across several neural systems in anatomical MR images of the brain.
Methods
We have developed an automated method to diagnose individuals as having one of various neuropsychiatric illnesses using only anatomical MRI scans. The method employs a semi-supervised learning algorithm that discovers natural groupings of brains based on the spatial patterns of variation in the morphology of the cerebral cortex and other brain regions. We used split-half and leave-one-out cross-validation analyses in large MRI datasets to assess the reproducibility and diagnostic accuracy of those groupings.
Results
In MRI datasets from persons with Attention-Deficit/Hyperactivity Disorder, Schizophrenia, Tourette Syndrome, Bipolar Disorder, or persons at high or low familial risk for Major Depressive Disorder, our method discriminated with high specificity and nearly perfect sensitivity the brains of persons who had one specific neuropsychiatric disorder from the brains of healthy participants and the brains of persons who had a different neuropsychiatric disorder.
Conclusions
Although the classification algorithm presupposes the availability of precisely delineated brain regions, our findings suggest that patterns of morphological variation across brain surfaces, extracted from MRI scans alone, can successfully diagnose the presence of chronic neuropsychiatric disorders. Extensions of these methods are likely to provide biomarkers that will aid in identifying biological subtypes of those disorders, predicting disease course, and individualizing treatments for a wide range of neuropsychiatric illnesses.
doi:10.1371/journal.pone.0050698
PMCID: PMC3517530  PMID: 23236384
10.  Volumetric MRI Markers and Predictors of Disease Activity in Early Multiple Sclerosis: A Longitudinal Cohort Study 
PLoS ONE  2012;7(11):e50101.
Objectives
To compare clinical and MRI parameters between patients with clinically isolated syndrome and those converting to clinically definite multiple sclerosis within 2 years, to identify volumetric MRI predictors of this conversion and to assess effect of early relapses.
Methods
The SET study comprised 220 patients with clinically isolated syndrome treated with interferon beta (mean age, 29 years; Expanded Disability Status Scale, 1.5). Three patients with missing data were excluded from the analysis. Physical disability, time to clinically definite multiple sclerosis and volumetric MRI data were recorded for 2 years.
Results
Patients reaching clinically definite multiple sclerosis showed impaired recovery of neurological function, faster decrease in corpus callosum cross-sectional area, higher T2 lesion volume and more contrast-enhancing lesions. Six-month decrease in corpus callosum cross-sectional area (≥1%) and baseline T2 lesion volume (≥5 cm3) predicted clinically definite multiple sclerosis within 2 years (hazard ratios 2.5 and 1.8, respectively). Of 22 patients fulfilling both predictive criteria, 83% reached clinically definite multiple sclerosis (hazard ratio 6.5). More relapses were associated with poorer recovery of neurological function and accelerated brain atrophy.
Conclusions
Neurological impairment is more permanent, brain atrophy is accelerated and focal inflammatory activity is greater in patients converting to clinically definite multiple sclerosis. Six-month corpus callosum atrophy and baseline T2 lesion volume jointly help predict individual risk of clinically definite multiple sclerosis. Early relapses contribute to permanent damage of the central nervous system.
doi:10.1371/journal.pone.0050101
PMCID: PMC3499512  PMID: 23166826
11.  Determining the Precise Cerebral Response to Acupuncture: An Improved fMRI Study 
PLoS ONE  2012;7(11):e49154.
Background
In acupuncture brain imaging trials, there are many non-acupuncture factors confounding the neuronal mapping. The modality of the placebo, subjects’ psychological attitude to acupuncture and their physical state are the three most confounding factors.
Objective
To obtain more precise and accurate cerebral fMRI mapping of acupuncture.
Design and Setting
A 2×2 randomized, controlled, participant-blinded cross-over factorial acupuncture trial was conducted at Xuanwu Hospital in Beijing, China.
Participants
Forty-one college students with myopia were recruited to participate in our study and were allocated randomly to four groups, Group A, Group B, Group C and Group D.
Interventions
Group A received real acupuncture (RA) and treatment instruction (TI); Group B received RA and non-treatment instruction (NI); Group C received sham acupuncture (SA) and TI; Group D received SA and NI.
Results
Stimulation at LR3 activated some areas of the visual cortex, and the cerebral response to non-acupuncture factors was complex and occurred in multiple areas.
Conclusions
The results provide more evidence regarding the credibility of acupuncture therapy and suggest that more precise experimental designs are needed to eliminate sources of bias in acupuncture controlled trials and to obtain sound results.
doi:10.1371/journal.pone.0049154
PMCID: PMC3494684  PMID: 23152865
12.  Diffusion Tensor Metrics as Biomarkers in Alzheimer's Disease 
PLoS ONE  2012;7(11):e49072.
Background
Although diffusion tensor imaging has been a major research focus for Alzheimer’s disease in recent years, it remains unclear whether it has sufficient stability to have biomarker potential. To date, frequently inconsistent results have been reported, though lack of standardisation in acquisition and analysis make such discrepancies difficult to interpret. There is also, at present, little knowledge of how the biometric properties of diffusion tensor imaging might evolve in the course of Alzheimer’s disease.
Methods
The biomarker question was addressed in this study by adopting a standardised protocol both for the whole brain (tract-based spatial statistics), and for a region of interest: the midline corpus callosum. In order to study the evolution of tensor changes, cross-sectional data from very mild (N = 21) and mild (N = 22) Alzheimer’s disease patients were examined as well as a longitudinal cohort (N = 16) that had been rescanned at 12 months.
Findings and Significance
The results revealed that increased axial and mean diffusivity are the first abnormalities to occur and that the first region to develop such significant differences was mesial parietal/splenial white matter; these metrics, however, remained relatively static with advancing disease indicating they are suitable as ‘state-specific’ markers. In contrast, increased radial diffusivity, and therefore decreased fractional anisotropy–though less detectable early–became increasingly abnormal with disease progression, and, in the splenium of the corpus callosum, correlated significantly with dementia severity; these metrics therefore appear ‘stage-specific’ and would be ideal for monitoring disease progression. In addition, the cross-sectional and longitudinal analyses showed that the progressive abnormalities in radial diffusivity and fractional anisotropy always occurred in areas that had first shown an increase in axial and mean diffusivity. Given that the former two metrics correlate with dementia severity, but the latter two did not, it would appear that increased axial diffusivity represents an upstream event that precedes neuronal loss.
doi:10.1371/journal.pone.0049072
PMCID: PMC3492261  PMID: 23145075
13.  Aberrant Resting-State Corticostriatal Functional Connectivity in Cirrhotic Patients with Hyperintense Globus Pallidus on T1-Weighted MR Imaging 
PLoS ONE  2012;7(11):e48886.
Neurobiological and neuroimaging studies have emphasized the structural and functional alterations in the striatum of cirrhotic patients, but alterations in the functional connections between the striatum and other brain regions have not yet been explored. Of note, manganese accumulation in the nervous system, frequently reflected by hyperintensity at the bilateral globus pallidus (GP) on T1-weighted imaging, has been considered a factor affecting the striatal and cortical functions in hepatic decompensation. We employed resting-state functional magnetic resonance imaging to analyze the temporal correlation between the striatum and the remaining brain regions using seed-based correlation analyses. The two-sample t-test was conducted to detect the differences in corticostriatal connectivity between 44 cirrhotic patients with hyperintensity at the bilateral GP and 20 healthy controls. Decreased connectivity of the caudate was detected in the anterior/middle cingulate gyrus, and increased connectivity of the caudate was found in the left motor cortex. A reduction in functional connectivity was found between the putamen and several regions, including the anterior cingulate gyrus, right insular lobe, inferior frontal gyrus, left parahippocampal gyrus, and anterior lobe of the right cerebellum; increased connectivity was detected between the putamen and right middle temporal gyrus. There were significant correlations between the corticostriatal connectivity and neuropsychological performances in the patient group, but not between the striatal connectivity and GP signal intensity. These alterations in the corticostriatal functional connectivity suggested the abnormalities in the intrinsic brain functional organiztion among the cirrhotic patients with manganese deposition, and may be associated with development of metabolic encephalopathy. The manganese deposition in nervous system, however, can not be an independent factor predicting the resting-state brain dysfunction in real time.
doi:10.1371/journal.pone.0048886
PMCID: PMC3492266  PMID: 23145011
14.  Concomitant Fractional Anisotropy and Volumetric Abnormalities in Temporal Lobe Epilepsy: Cross-Sectional Evidence for Progressive Neurologic Injury 
PLoS ONE  2012;7(10):e46791.
Background
In patients with temporal lobe epilepsy and associated hippocampal sclerosis (TLEhs) there are brain abnormalities extending beyond the presumed epileptogenic zone as revealed separately in conventional magnetic resonance imaging (MRI) and MR diffusion tensor imaging (DTI) studies. However, little is known about the relation between macroscopic atrophy (revealed by volumetric MRI) and microstructural degeneration (inferred by DTI).
Methodology/Principal Findings
For 62 patients with unilateral TLEhs and 68 healthy controls, we determined volumes and mean fractional anisotropy (FA) of ipsilateral and contralateral brain structures from T1-weighted and DTI data, respectively. We report significant volume atrophy and FA alterations of temporal lobe, subcortical and callosal regions, which were more diffuse and bilateral in patients with left TLEhs relative to right TLEhs. We observed significant relationships between volume loss and mean FA, particularly of the thalamus and putamen bilaterally. When corrected for age, duration of epilepsy was significantly correlated with FA loss of an anatomically plausible route - including ipsilateral parahippocampal gyrus and temporal lobe white matter, the thalamus bilaterally, and posterior regions of the corpus callosum that contain temporal lobe fibres - that may be suggestive of progressive brain degeneration in response to recurrent seizures.
Conclusions/Significance
Chronic TLEhs is associated with interrelated DTI-derived and volume-derived brain degenerative abnormalities that are influenced by the duration of the disorder and the side of seizure onset. This work confirms previously contradictory findings by employing multi-modal imaging techniques in parallel in a large sample of patients.
doi:10.1371/journal.pone.0046791
PMCID: PMC3469561  PMID: 23071638
15.  Cortico-Cardio-Respiratory Network Interactions during Anesthesia 
PLoS ONE  2012;7(9):e44634.
General anesthetics are used during medical and surgical procedures to reversibly induce a state of total unconsciousness in patients. Here, we investigate, from a dynamic network perspective, how the cortical and cardiovascular systems behave during anesthesia by applying nonparametric spectral techniques to cortical electroencephalography, electrocardiogram and respiratory signals recorded from anesthetized rats under two drugs, ketamine-xylazine (KX) and pentobarbital (PB). We find that the patterns of low-frequency cortico-cardio-respiratory network interactions may undergo significant changes in network activity strengths and in number of network links at different depths of anesthesia dependent upon anesthetics used.
doi:10.1371/journal.pone.0044634
PMCID: PMC3446920  PMID: 23028572
16.  Approach-Bias Predicts Development of Cannabis Problem Severity in Heavy Cannabis Users: Results from a Prospective FMRI Study 
PLoS ONE  2012;7(9):e42394.
A potentially powerful predictor for the course of drug (ab)use is the approach-bias, that is, the pre-reflective tendency to approach rather than avoid drug-related stimuli. Here we investigated the neural underpinnings of cannabis approach and avoidance tendencies. By elucidating the predictive power of neural approach-bias activations for future cannabis use and problem severity, we aimed at identifying new intervention targets. Using functional Magnetic Resonance Imaging (fMRI), neural approach-bias activations were measured with a Stimulus Response Compatibility task (SRC) and compared between 33 heavy cannabis users and 36 matched controls. In addition, associations were examined between approach-bias activations and cannabis use and problem severity at baseline and at six-month follow-up. Approach-bias activations did not differ between heavy cannabis users and controls. However, within the group of heavy cannabis users, a positive relation was observed between total lifetime cannabis use and approach-bias activations in various fronto-limbic areas. Moreover, approach-bias activations in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) independently predicted cannabis problem severity after six months over and beyond session-induced subjective measures of craving. Higher DLPFC/ACC activity during cannabis approach trials, but lower activity during cannabis avoidance trials were associated with decreases in cannabis problem severity. These findings suggest that cannabis users with deficient control over cannabis action tendencies are more likely to develop cannabis related problems. Moreover, the balance between cannabis approach and avoidance responses in the DLPFC and ACC may help identify individuals at-risk for cannabis use disorders and may be new targets for prevention and treatment.
doi:10.1371/journal.pone.0042394
PMCID: PMC3434213  PMID: 22957019
17.  Improved Sensitivity to Cerebral White Matter Abnormalities in Alzheimer’s Disease with Spherical Deconvolution Based Tractography 
PLoS ONE  2012;7(8):e44074.
Diffusion tensor imaging (DTI) based fiber tractography (FT) is the most popular approach for investigating white matter tracts in vivo, despite its inability to reconstruct fiber pathways in regions with “crossing fibers.” Recently, constrained spherical deconvolution (CSD) has been developed to mitigate the adverse effects of “crossing fibers” on DTI based FT. Notwithstanding the methodological benefit, the clinical relevance of CSD based FT for the assessment of white matter abnormalities remains unclear. In this work, we evaluated the applicability of a hybrid framework, in which CSD based FT is combined with conventional DTI metrics to assess white matter abnormalities in 25 patients with early Alzheimer’s disease. Both CSD and DTI based FT were used to reconstruct two white matter tracts: one with regions of “crossing fibers,” i.e., the superior longitudinal fasciculus (SLF) and one which contains only one fiber orientation, i.e. the midsagittal section of the corpus callosum (CC). The DTI metrics, fractional anisotropy (FA) and mean diffusivity (MD), obtained from these tracts were related to memory function. Our results show that in the tract with “crossing fibers” the relation between FA/MD and memory was stronger with CSD than with DTI based FT. By contrast, in the fiber bundle where one fiber population predominates, the relation between FA/MD and memory was comparable between both tractography methods. Importantly, these associations were most pronounced after adjustment for the planar diffusion coefficient, a measure reflecting the degree of fiber organization complexity. These findings indicate that compared to conventionally applied DTI based FT, CSD based FT combined with DTI metrics can increase the sensitivity to detect functionally significant white matter abnormalities in tracts with complex white matter architecture.
doi:10.1371/journal.pone.0044074
PMCID: PMC3432077  PMID: 22952880
18.  Reduced Neural Synchrony in Patients with Restless Legs Syndrome during a Visual Oddball Task 
PLoS ONE  2012;7(7):e42312.
Background
Restless legs syndrome (RLS) is a sensorimotor neurological disorder characterized by an irresistible urge to move the legs. It has been reported that RLS patients show cognitive deficits, presumably due to hyperactivity causing loss of attention, or malfunctions in the frontal region resulting from sleep deprivation. However, the mechanism underlying cognitive deficits in RLS patients is mostly unknown. As an effort to clarifying this, we investigated the differences in neural activity and phase synchrony between healthy controls and RLS patients during cognitive task performances.
Methodology/Principal Findings
Seventeen female drug-naive RLS patients were enrolled in the study, and an age-matched group of thirteen healthy female volunteers served as controls. Multichannel event-related potentials (ERPs) were recorded from RLS patients and normal controls while performing a visual oddball task. In addition to conventional analyses of ERP waveforms and spectra, interregional gamma-band phase synchrony (GBPS) was investigated to observe the differences in interregional neural synchronies between normal and RLS patient groups. Strong GBPS was observed primarily between anterior and posterior regions along the midline for both groups. Along with significant reduction and delay of P300 ERP and induced gamma-band activity (GBA), the GBPS was considerably decreased in RLS patients compared to normal subjects, especially at frontal region.
Conclusions
Overall, our results support that cognitive dysfunction in RLS patients is associated with reduced interregional neural synchrony as well as alterations in local neural activity.
doi:10.1371/journal.pone.0042312
PMCID: PMC3407084  PMID: 22848757
19.  Functional Anatomy of the Masking Level Difference, an fMRI Study 
PLoS ONE  2012;7(7):e41263.
Introduction
Masking level differences (MLDs) are differences in the hearing threshold for the detection of a signal presented in a noise background, where either the phase of the signal or noise is reversed between ears. We use N0/Nπ to denote noise presented in-phase/out-of-phase between ears and S0/Sπ to denote a 500 Hz sine wave signal as in/out-of-phase. Signal detection level for the noise/signal combinations N0Sπ and NπS0 is typically 10–20 dB better than for N0S0. All combinations have the same spectrum, level, and duration of both the signal and the noise.
Methods
Ten participants (5 female), age: 22–43, with N0Sπ-N0S0 MLDs greater than 10 dB, were imaged using a sparse BOLD fMRI sequence, with a 9 second gap (1 second quiet preceding stimuli). Band-pass (400–600 Hz) noise and an enveloped signal (.25 second tone burst, 50% duty-cycle) were used to create the stimuli. Brain maps of statistically significant regions were formed from a second-level analysis using SPM5.
Results
The contrast NπS0- N0Sπ had significant regions of activation in the right pulvinar, corpus callosum, and insula bilaterally. The left inferior frontal gyrus had significant activation for contrasts N0Sπ-N0S0 and NπS0-N0S0. The contrast N0S0-N0Sπ revealed a region in the right insula, and the contrast N0S0-NπS0 had a region of significance in the left insula.
Conclusion
Our results extend the view that the thalamus acts as a gating mechanism to enable dichotic listening, and suggest that MLD processing is accomplished through thalamic communication with the insula, which communicate across the corpus callosum to either enhance or diminish the binaural signal (depending on the MLD condition). The audibility improvement of the signal with both MLD conditions is likely reflected by activation in the left inferior frontal gyrus, a late stage in the what/where model of auditory processing.
doi:10.1371/journal.pone.0041263
PMCID: PMC3407245  PMID: 22848453
20.  Is Payoff Necessarily Weighted by Probability When Making a Risky Choice? Evidence from Functional Connectivity Analysis 
PLoS ONE  2012;7(7):e41048.
How people make decisions under risk remains an as-yet-unresolved but fundamental question. Mainstream theories about risky decision making assume that the core processes involved in reaching a risky decision include weighting each payoff or reward magnitude by its probability and then summing the outcomes. However, recently developed theories question whether payoffs are necessarily weighted by probability when making a risky choice. Using functional connectivity analysis, we aimed to provide neural evidence to answer whether this key assumption of computing expectations holds when making a risky choice. We contrasted a trade-off instruction choice that required participants to integrate probability and payoff information with a preferential choice that did not. Based on the functional connectivity patterns between regions in which activity was detected during both of the decision-making tasks, we classified the regions into two networks. One network includes primarily the left and right lateral prefrontal cortices and posterior parietal cortices, which were found to be related to probability in previous reports, and the other network is composed of the bilateral basal ganglia, which have been implicated in payoff. We also found that connectivity between the payoff network and some regions in the probability network (including the left lateral prefrontal cortices and bilateral inferior parietal lobes) were stronger during the trade-off instruction choice task than during the preferential choice task. This indicates that the functional integration between the probability and payoff networks during preferential choice was not as strong as the integration during trade-off instruction choice. Our results provide neural evidence that the weighting process uniformly predicted by the mainstream theory is unnecessary during preferential choice. Thus, our functional integration findings can provide a new direction for the investigation of the principles of risky decision making.
doi:10.1371/journal.pone.0041048
PMCID: PMC3398869  PMID: 22815908
21.  Chloridobis[2-(1,3-thia­zol-4-yl-κN)-1H-benzimidazole-κN 3]cobalt(II) chloride dihydrate 
In the title compound, [CoCl(C10H7N3S)2]Cl·2H2O, the CoII atom is five-coordinated by four N atoms from two chelating 2-(1,3-thia­zol-4-yl)-1H-benzimidazole ligands and one Cl atom in a distorted trigonal–bipyramidal geometry. In the crystal, N—H⋯O and O—H⋯Cl hydrogen bonds and π–π inter­actions between the thia­zole, imidazole and benzene rings [centroid-to-centroid distances 3.546 (2), 3.683 (2) and 3.714 (2) Å] link the complex cations, chloride anions and uncoordinating water mol­ecules into a three-dimensional network.
doi:10.1107/S1600536812030371
PMCID: PMC3414112  PMID: 22904719
22.  Working Memory Impairment in Fibromyalgia Patients Associated with Altered Frontoparietal Memory Network 
PLoS ONE  2012;7(6):e37808.
Background
Fibromyalgia (FM) is a disorder characterized by chronic widespread pain and frequently associated with other symptoms. Patients with FM commonly report cognitive complaints, including memory problem. The objective of this study was to investigate the differences in neural correlates of working memory between FM patients and healthy subjects, using functional magnetic resonance imaging (MRI).
Methodology/Principal Findings
Nineteen FM patients and 22 healthy subjects performed an n-back memory task during MRI scan. Functional MRI data were analyzed using within- and between-group analysis. Both activated and deactivated brain regions during n-back task were evaluated. In addition, to investigate the possible effect of depression and anxiety, group analysis was also performed with depression and anxiety level in terms of Beck depression inventory (BDI) and Beck anxiety inventory (BAI) as a covariate. Between-group analyses, after controlling for depression and anxiety level, revealed that within the working memory network, inferior parietal cortex was strongly associated with the mild (r = 0.309, P = 0.049) and moderate (r = 0.331, P = 0.034) pain ratings. In addition, between-group comparison revealed that within the working memory network, the left DLPFC, right VLPFC, and right inferior parietal cortex were associated with the rating of depression and anxiety?
Conclusions/Significance
Our results suggest that the working memory deficit found in FM patients may be attributable to differences in neural activation of the frontoparietal memory network and may result from both pain itself and depression and anxiety associated with pain.
doi:10.1371/journal.pone.0037808
PMCID: PMC3370998  PMID: 22715371
23.  Subarachnoid Space: New Tricks by an Old Dog 
PLoS ONE  2012;7(5):e37529.
Purpose
The purpose of the study was to: (1) evaluate the subarachnoid space (SAS) width and pial artery pulsation in both hemispheres, and (2) directly compare magnetic resonance imaging (MRI) to near-infrared transillumination/backscattering sounding (NIR-T/BSS) measurements of SAS width changes in healthy volunteers.
Methods
The study was performed on three separate groups of volunteers, consisting in total of 62 subjects (33 women and 29 men) aged from 16 to 39 years. SAS width was assessed by MRI and NIR-T/BSS, and pial artery pulsation by NIR-T/BSS.
Results
In NIR-T/BSS, the right frontal SAS was 9.1% wider than the left (p<0.01). The SAS was wider in men (p<0.01), while the pial artery pulsation was higher in women (p<0.01). Correlation and regression analysis of SAS width changes between the back- and abdominal-lying positions measured with MRI and NIRT-B/SS demonstrated high interdependence between both methods (r = 0.81, p<0.001).
Conclusions
NIR-T/BSS and MRI were comparable and gave equivalent modalities for the SAS width change measurements. The SAS width and pial artery pulsation results obtained with NIR-T/BSS are consistent with the MRI data in the literature related to sexual dimorphism and morphological asymmetries between the hemispheres. NIR-T/BSS is a potentially cheap and easy-to-use method for early screening in patients with brain tumours, increased intracranial pressures and other abnormalities. Further studies in patients with intracranial pathologies are warranted.
doi:10.1371/journal.pone.0037529
PMCID: PMC3365109  PMID: 22701518
24.  Age-Specific Characteristics and Coupling of Cerebral Arterial Inflow and Cerebrospinal Fluid Dynamics 
PLoS ONE  2012;7(5):e37502.
The objective of this work is to quantify age-related differences in the characteristics and coupling of cerebral arterial inflow and cerebrospinal fluid (CSF) dynamics. To this end, 3T phase-contrast magnetic resonance imaging blood and CSF flow data of eleven young ( years) and eleven elderly subjects ( years) with a comparable sex-ratio were acquired. Flow waveforms and their frequency composition, transfer functions from blood to CSF flows and cross-correlations were analyzed. The magnitudes of the frequency components of CSF flow in the aqueduct differ significantly between the two age groups, as do the frequency components of the cervical spinal CSF and the arterial flows. The males' aqueductal CSF stroke volumes and average flow rates are significantly higher than those of the females. Transfer functions and cross-correlations between arterial blood and CSF flow reveal significant age-dependence of phase-shift between these, as do the waveforms of arterial blood, as well as cervical-spinal and aqueductal CSF flows. These findings accentuate the need for age- and sex-matched control groups for the evaluation of cerebral pathologies such as hydrocephalus.
doi:10.1371/journal.pone.0037502
PMCID: PMC3364266  PMID: 22666360
25.  The Impact of Social Disparity on Prefrontal Function in Childhood 
PLoS ONE  2012;7(4):e35744.
The prefrontal cortex (PFC) develops from birth through late adolescence. This extended developmental trajectory provides many opportunities for experience to shape the structure and function of the PFC. To date, a few studies have reported links between parental socioeconomic status (SES) and prefrontal function in childhood, raising the possibility that aspects of environment associated with SES impact prefrontal function. Considering that behavioral measures of prefrontal function are associated with learning across multiple domains, this is an important area of investigation. In this study, we used fMRI to replicate previous findings, demonstrating an association between parental SES and PFC function during childhood. In addition, we present two hypothetical mechanisms by which SES could come to affect PFC function of this association: language environment and stress reactivity. We measured language use in the home environment and change in salivary cortisol before and after fMRI scanning. Complexity of family language, but not the child's own language use, was associated with both parental SES and PFC activation. Change in salivary cortisol was also associated with both SES and PFC activation. These observed associations emphasize the importance of both enrichment and adversity-reduction interventions in creating good developmental environments for all children.
doi:10.1371/journal.pone.0035744
PMCID: PMC3338535  PMID: 22563395

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