Neuromelanin-sensitive MRI correlates of cognitive and motor function in Parkinson's disease with freezing of gait.

Substantia nigra pars compacta (SNc) and locus coeruleus (LC) are neuromelanin-rich nuclei implicated in diverse cognitive and motor processes in normal brain function and disease. However, their roles in aging and neurodegenerative disease mechanisms have remained unclear due to a lack of tools to study them in vivo. Preclinical and post-mortem human investigations indicate that the relationship between tissue neuromelanin content and neurodegeneration is complex. Neuromelanin exhibits both neuroprotective and cytotoxic characteristics, and tissue neuromelanin content varies across the lifespan, exhibiting an inverted U-shaped relationship with age. Neuromelanin-sensitive MRI (NM-MRI) is an emerging modality that allows measurement of neuromelanin-associated contrast in SNc and LC in humans. NM-MRI robustly detects disease effects in these structures in neurodegenerative and psychiatric conditions, including Parkinson's disease (PD). Previous NM-MRI studies of PD have largely focused on detecting disease group effects, but few studies have reported NM-MRI correlations with phenotype. Because neuromelanin dynamics are complex, we hypothesize that they are best interpreted in the context of both disease stage and aging, with neuromelanin loss correlating with symptoms most clearly in advanced stages where neuromelanin loss and neurodegeneration are coupled. We tested this hypothesis using NM-MRI to measure SNc and LC volumes in healthy older adult control individuals and in PD patients with and without freezing of gait (FOG), a severe and disabling PD symptom. We assessed for group differences and correlations between NM-MRI measures and aging, cognition and motor deficits. SNc volume was significantly decreased in PD with FOG compared to controls. SNc volume correlated significantly with motor symptoms and cognitive measures in PD with FOG, but not in PD without FOG. SNc volume correlated significantly with aging in PD. When PD patients were stratified by disease duration, SNc volume correlated with aging, cognition, and motor deficits only in PD with disease duration >5 years. We conclude that in severe or advanced PD, identified by either FOG or disease duration >5 years, the observed correlations between SNc volume and aging, cognition, and motor function may reflect the coupling of neuromelanin loss with neurodegeneration and the associated emergence of a linear relationship between NM-MRI measures and phenotype.

Kynurenines increase MRS metabolites in basal ganglia and decrease resting-state connectivity in frontostriatal reward circuitry in depression.

Inflammation is associated with the development of anhedonia in major depression (MD), but the pathway by which inflammatory molecules gain access to the brain and lead to anhedonia is not clear. Molecules of the kynurenine pathway (KP), which is activated by inflammation, readily influx into the brain and generate end products that alter brain chemistry, disrupt circuit functioning, and result in the expression of inflammatory behaviors such as anhedonia. We examined the impact of plasma and CSF KP metabolites on brain chemistry and neural function using multimodal neuroimaging in 49 depressed subjects. We measured markers of glial dysfunction and distress including glutamate (Glu) and myo-inositol in the left basal ganglia using magnetic resonance spectroscopy (MRS); metrics of local activity coherence (regional homogeneity, ReHo) and functional connectivity from resting-state functional MRI measures; and anhedonia from the Inventory for Depressive Symptoms-Self Report Version (IDS-SR). Plasma kynurenine/tryptophan (KYN/TRP) ratio and cerebrospinal fluid (CSF) 3-hydroxykynurenine (3HK) were associated with increases in left basal ganglia myo-inositol. Plasma kynurenic acid (KYNA) and KYNA/QA were associated with decreases and quinolinic acid (QA) with increases in left basal ganglia Glu. Plasma and CSF KP were associated with decreases in ReHo in the basal ganglia and dorsomedial prefrontal regions (DMPFC) and impaired functional connectivity between these two regions. DMPFC-basal ganglia mediated the effect of plasma and CSF KP on anhedonia. These findings highlight the pathological impact of KP system dysregulation in mediating inflammatory behaviors such as anhedonia.

Protein and gene markers of metabolic dysfunction and inflammation together associate with functional connectivity in reward and motor circuits in depression.

Bidirectional relationships between inflammation and metabolic dysfunction may contribute to the pathophysiology of psychiatric illnesses like depression. Metabolic disturbances drive inflammation, which in turn exacerbate metabolic outcomes including insulin resistance. Both inflammatory (e.g. endotoxin, vaccination) and metabolic challenges (e.g. glucose ingestion) have been shown to affect activity and functional connectivity (FC) in brain regions that subserve reward and motor processing. We previously reported relationships between elevated concentrations of endogenous inflammatory markers including C-reactive protein (CRP) and low corticostriatal FC, which correlated with symptoms of anhedonia and motor slowing in major depression (MD). Herein, we examined whether similar relationships were observed between plasma markers related to glucose metabolism (non-fasting concentrations of glucose, insulin, leptin, adiponectin and resistin) in 42 medically-stable, unmedicated MD outpatients who underwent fMRI. A targeted, hypothesis-driven approach was used to assess FC between seeds in subdivisions of the ventral and dorsal striatum and a region in ventromedial prefrontal cortex (VS-vmPFC), which was previously found to correlate with both inflammation and symptoms of anhedonia and motor slowing. Associations between FC and gene expression signatures were also explored. A composite score of all 5 glucose-related markers (with increasing values reflecting higher concentrations) was negatively correlated with both ventral striatum (VS)-vmPFC (r = -0.33, p < 0.05) and dorsal caudal putamen (dcP)-vmPFC (r = -0.51, p < 0.01) FC, and remained significant after adjusting for covariates including body mass index (p < 0.05). Moreover, an interaction between the glucose-related composite score and CRP was observed for these relationships (F[2,33] = 4.3, p < 0.05) whereby significant correlations between the glucose-related metabolic markers and FC was found only in patients with high plasma CRP (>3 mg/L; r = -0.61 to -0.81, p < 0.05). Insulin and resistin were the individual markers most predictive of VS-vmPFC and dcP-mPFC FC, respectively, and insulin, resistin and CRP clustered together and in association with both LV-vmPFC and dcP-vmPFC in principal component analyses. Exploratory whole blood gene expression analyses also confirmed that gene probes negatively associated with FC were enriched for both inflammatory and metabolic pathways (FDR p < 0.05). These results provide preliminary evidence that inflammation and metabolic dysfunction contribute jointly to deficits in reward and motor circuits in MD. Future studies using fasting samples and longitudinal and interventional approaches are required to further elucidate the respective contributions of inflammation and metabolic dysfunction to circuits and symptoms relevant to motivation and motor activity, which may have treatment implications for patients with psychiatric illnesses like depression.

Increased inflammation and brain glutamate define a subtype of depression with decreased regional homogeneity, impaired network integrity, and anhedonia.

Combined increases in peripheral inflammation and brain glutamate may identify a subtype of depression with distinct neuroimaging signatures. Two contrasting subgroups of depressed subjects-with and without combined elevations in plasma C-reactive protein (CRP) and basal ganglia glutamate (high and low CRP-Glu, respectively) were identified by hierarchical clustering using plasma CRP (indexing peripheral inflammation) and magnetic resonance spectroscopy (MRS)-based measurement of left basal ganglia glutamate. High CRP-Glu group status was associated with greater severity of anhedonia and cognitive and motor slowing. Local- and network-level measures of functional integrity were determined using brain oxygen level-dependent (BOLD)-oscillatory activity and graph theory. Greater decreases in concordance of oscillatory activity between neighboring voxels (Regional Homogeneity 'ReHo', p < 0.01) within the MRS volume-of-interest was associated with the High CRP-Glu subgroup. Using brain-wide, CRP-Glu ReHo contrast maps, a covariance network of 41 regions-of-interest (ROIs) with similar ReHo decreases was identified in the High CRP-Glu group and was located to brain structures previously implicated in depression. The 41-ROI network was further decomposed into four subnetworks. ReHo decreases within Subnetwork4-comprised of reward processing regions -was associated with anhedonia. Subnetwork4 ReHo also predicted decreased network integrity, which mediated the link between local ReHo and anhedonia in the Low but not High CRP-Glu group. These findings suggest that decreased ReHo and related disruptions in network integrity may reflect toxic effects of inflammation-induced increases in extrasynaptic glutamate signaling. Moreover, local BOLD oscillatory activity as reflected in ReHo might be a useful measure of target-engagement in the brain for treatment of inflammation-induced behaviors.

Intranasal oxytocin modulates neural functional connectivity during human social interaction.

Oxytocin (OT) modulates social behavior in primates and many other vertebrate species. Studies in non-primate animals have demonstrated that, in addition to influencing activity within individual brain areas, OT influences functional connectivity across networks of areas involved in social behavior. Previously, we used fMRI to image brain function in human subjects during a dyadic social interaction task following administration of either intranasal oxytocin (INOT) or placebo, and analyzed the data with a standard general linear model. Here, we conduct an extensive re-analysis of these data to explore how OT modulates functional connectivity across a neural network that animal studies implicate in social behavior. OT induced widespread increases in functional connectivity in response to positive social interactions among men and widespread decreases in functional connectivity in response to negative social interactions among women. Nucleus basalis of Meynert, an important regulator of selective attention and motivation with a particularly high density of OT receptors, had the largest number of OT-modulated connections. Regions known to receive mesolimbic dopamine projections such as the nucleus accumbens and lateral septum were also hubs for OT effects on functional connectivity. Our results suggest that the neural mechanism by which OT influences primate social cognition may include changes in patterns of activity across neural networks that regulate social behavior in other animals.

Arginine Vasopressin Effects on Subjective Judgments and Neural Responses to Same and Other-Sex Faces in Men and Women.

Arginine vasopressin (AVP) influences social and emotional behaviors across a wide range of species. In humans, intranasal AVP has been previously shown to alter physiological responses to and subjective judgments of same-sex faces in both men and women. The present study attempted to elucidate the neural mechanism for these effects by randomizing 40 healthy men and 40 healthy women to treatment with either 40 IU intranasal AVP or a saline placebo approximately 30 min before imaging their brain function with fMRI as they viewed same and other-sex faces. All subjects were also scanned a second time several days later with no treatment to evaluate the persistence of AVP effects over time. AVP acutely increased positive ratings of same-sex faces in women, with some evidence that these effects persisted until the second scan. While AVP had no acute effects on same-sex ratings in men, AVP increased positive ratings of same-sex faces several days later. On the other hand, AVP had no effect on other-sex face judgments in either sex. AVP modulation of brain function was focused on the nucleus accumbens (NAc) and the lateral septum, two reward processing areas involved in the formation of social bonds. AVP provoked acute increases in right NAc and bilateral lateral septum responses to female faces among men, with left lateral septum responses persisting over time while right NAc responses reversed over time. Finally, AVP modulated hypothalamic activation to faces in both men and women. The present study therefore indicates that intranasal AVP affects subjective ratings and neural responses to same and other-sex faces in men and women, with some effects persisting and others emerging over time. Future studies should investigate whether AVP effects are modulated by individual variables such as genotype, personality, or attachment style as previously reported for other nonapeptides.

Diffusion tensor imaging of the substantia nigra in Parkinson's disease revisited.

OBJECTIVE: To analyze diffusion tensor imaging (DTI) data in the substantia nigra (SN) using a more consistent region of interest (ROI) defined by neuromelanin-sensitive MRI in order to assess Parkinson's disease (PD) related changes in diffusion characteristics in the SN. METHODS: T1 -weighted and DTI data were obtained in a cohort of 37 subjects (17 control subjects and 20 subjects with PD). The subjects in the PD group were clinically diagnosed PD patients with an average Unified Parkinsonian Disease Rating Scale (UPDRS)-III score of 23.2 ± 9.3. DTI data were analyzed using SN ROIs defined by neuromelanin-sensitive MRI and, for comparison, with ROIs defined on T2 -weighted images (b = 0 images). RESULTS: Compared with control subjects, significantly lower fractional anisotropy was observed in PD in the neuromelanin SN ROI but not in the ROI derived from the T2 -weighted image. This decrease was largest in the rostral and lateral portions of the neuromelanin volume, which were found to have more hypointensity in the T2 -weighted image and, presumably, higher iron content in the PD group. In addition, a larger decrease in fractional anisotropy was seen in the SN region of interest on the side contralateral to the side exhibiting more severe symptoms. These results indicate that the use of neuromelanin sensitive MRI to define the ROI in the SN for analyzing DTI data leads to more significant results, enhancing the robustness of DTI study and DTI based biomarkers of PD. Hum Brain Mapp 37:2547-2556, 2016. © 2016 Wiley Periodicals, Inc.

Spatiotemporal Modeling of Brain Dynamics Using Resting-State Functional Magnetic Resonance Imaging with Gaussian Hidden Markov Model.

Analyzing functional magnetic resonance imaging (fMRI) time courses with dynamic approaches has generated a great deal of interest because of the additional temporal features that can be extracted. In this work, to systemically model spatiotemporal patterns of the brain, a Gaussian hidden Markov model (GHMM) was adopted to model the brain state switching process. We assumed that the brain switches among a number of different brain states as a Markov process and used multivariate Gaussian distributions to represent the spontaneous activity patterns of brain states. This model was applied to resting-state fMRI data from 100 subjects in the Human Connectome Project and detected nine highly reproducible brain states and their temporal and transition characteristics. Our results indicate that the GHMM can unveil brain dynamics that may provide additional insights regarding the brain at resting state.

A multicontrast approach for comprehensive imaging of substantia nigra.

We characterize the contrast behavior of substantia nigra (SN) in both magnetization transfer (MT) imaging, which is believed to be sensitive to neuromelanin (NM), and susceptibility weighted imaging (SWI). Images were acquired with a MT prepared dual echo gradient echo sequence. The first echo was taken as the MT contrast image and the second was used to generate the SWI image. SN volumes were segmented from these two types of images using a thresholding method. The spatial and signal characteristics of the extracted SWI and MT volumes were compared. Both images showed the presence of SN but the volumes of the SN identified in the two are spatially incongruent. The MT volume was more caudal than the SWI volume and with only a 12% overlap between the two volumes. Considering the SN volumes in each hemisphere separately, the average distances between the centers of mass of the volumes from the two types images are 5.1±1.1mm and 4.1±1.2mm, respectively. The frequency offsets (homodyne filtered phase/echo time) for the volumes derived from MT (NM) images and SWI images are 0.09±0.32radians/s and -1.12±0.57radians/s (p<0.0001), respectively. The MT contrasts for the two volumes are 0.16±0.02 and 0.10±0.03 (p<0.001), respectively. Our results indicate that the two contrasts are sensitive to different portions of the SN, with MT seeing the more caudal portion of the SN than SWI, likely due to variations of NM and iron content in the SN. Despite the small overlap, these regions are complementary. Our results provide a new understanding of the contrast behavior of the SN in the two imaging approaches commonly used to image it and indicate that using both may yield a more comprehensive visualization of the SN.

Age-related increases in basal ganglia glutamate are associated with TNF, reduced motivation and decreased psychomotor speed during IFN-alpha treatment: Preliminary findings.

Inflammation-induced alterations in central nervous system (CNS) metabolism have focused on glutamate. At excessive concentrations, glutamate is toxic to glia and neurons, and inflammatory cytokines have been shown to influence glutamate turnover by blocking glutamate reuptake and increasing glutamate release. Increased glutamate has also been found in depression, a disorder associated with increased inflammation. Data by our group have shown increased glutamate as measured by magnetic resonance spectroscopy (MRS) in basal ganglia and dorsal anterior cingulate cortex of patients administered the inflammatory cytokine interferon (IFN)-alpha. Given data that increasing age is associated with an exaggerated CNS inflammatory response, we examined whether older age (>55years) would be associated with a greater IFN-alpha-induced increase in CNS glutamate. Using a longitudinal design, 31 patients with hepatitis C virus (HCV) underwent MRS, blood sampling for inflammatory markers, and behavioral assessments before (Visit 1) and after 4weeks (Visit 2) of either IFN-alpha (n=17) or no treatment (n=14). Older patients treated with IFN-alpha exhibited a significantly greater increase in glutamate from Visit 1 to Visit 2 as reflected by the glutamate/creatine ratio (Glu/Cr) in left basal ganglia compared to older controls and younger IFN-alpha-treated and untreated subjects. In addition, increased Glu/Cr in older but not younger IFN-alpha-treated and untreated patients was associated with increased tumor necrosis factor, reduced motivation as measured by the Multidimensional Fatigue Inventory and increased choice movement time on the Cambridge Neuropsychological Test Automated Battery. Taken together, these preliminary data support the notion that older age may interact with inflammation to exaggerate the effects of inflammatory stimuli on CNS glutamate and behavior.

Simultaneous imaging of locus coeruleus and substantia nigra with a quantitative neuromelanin MRI approach.

Quantitative MRI of neuromelanin (NM) containing structures (referred to as NM-MRI) in the brainstem, namely the locus coeruleus (LC) and substantia nigra (SN), may assist with the early detection of Parkinson's disease (PD) and Alzheimer's disease (AD) as well as differential diagnosis in the early disease stages. In this study, two gradient echo (GRE) sequences with magnetization transfer contrast (MTC) preparation pulses were developed to simultaneously image the LC and SN. This has been a challenge with NM-MRI techniques used in previous studies due to the relatively high specific absorption rate (SAR) induced by these techniques. In addition, a semi-automated quantitative analysis scheme was applied to estimate volumes and contrast-to-noise ratios (CNR) of the LC and SN based on segmentation of both structures. Compared to a T1-weighted turbo spin echo (TSE) sequence typically used for simultaneous imaging of the LC and SN, the two GRE-MTC sequences exhibited improved performance in terms of higher sensitivity (in CNR) in imaging the SN and lower SAR during the scans. A multiple-measurement protocol was adopted as well so that motion degraded measurements could be removed and artifacts associated with motion could be corrected. The present approach has demonstrated advantages in image acquisition (lower SAR and higher sensitivity), image pre-processing (with motion correction) and quantitative image analysis (segmentation-based estimation of volume and CNR) when compared with existing NM-MRI approaches. This approach has potential for detection and monitoring of neurodegeneration in LC and SN in disease states including AD and PD.

IFN-alpha-induced cortical and subcortical glutamate changes assessed by magnetic resonance spectroscopy.

Cytokine effects on behavior may be related to alterations in glutamate metabolism. We therefore measured glutamate concentrations in brain regions shown to be affected by inflammatory stimuli including the cytokine interferon (IFN)-alpha. IFN-alpha is known to alter neural activity in the dorsal anterior cingulate cortex (dACC) and basal ganglia in association with symptoms of depression and increases in peripheral cytokines including the tumor necrosis factor (TNF) and its soluble receptor. Single-voxel magnetic resonance spectroscopy (MRS) was employed to measure glutamate concentrations normalized to creatine (Glu/Cr) in dACC and basal ganglia of 31 patients with hepatitis C before and after ∼ 1 month of either no treatment (n = 14) or treatment with IFN-alpha (n = 17). Depressive symptoms were measured at each visit using the Inventory of Depressive Symptoms-Clinician Rating (IDS-C) and the Multidimensional Fatigue Inventory. IFN-alpha was associated with a significant increase in Glu/Cr in dACC and left basal ganglia. Increases in dACC Glu/Cr were positively correlated with scores on the IDS-C in the group as a whole, but not in either group alone. Glu/Cr increases in left basal ganglia were correlated with decreased motivation in the group as a whole and in IFN-alpha-treated subjects alone. No Glu/Cr changes were found in the right basal ganglia, and no significant correlations were found between Glu/Cr and the inflammatory markers. IFN-alpha-induced increases in glutamate in dACC and basal ganglia are consistent with MRS findings in bipolar depression and suggest that inflammatory cytokines may contribute to glutamate alterations in patients with mood disorders and increased inflammation.

Understanding specific effects of prenatal alcohol exposure on brain structure in young adults.

Prenatal alcohol exposure (PAE) is associated with various adverse effects on human brain and behavior. Recently, neuroimaging studies have begun to identify PAE effects on specific brain structures. Investigation of such specific PAE effects is important for understanding the teratogenic mechanism of PAE on human brain, which is critical for differentiating PAE from other disorders. In this structural MRI study with young adults, PAE effects on the volumes of automatically segmented cortical and subcortical regions of interest (ROIs) were evaluated both through a group difference approach and a parametric approach. In the group difference approach (comparing among two PAE and a control groups), a disproportionate PAE effect was found in several occipital and temporal regions. This result is inconsistent with previous studies with child samples. Moreover, a gender difference in PAE effect was shown in some cortical ROIs. These findings suggest that sampling and gender may be important factors for interpreting specific PAE effects on human brain. With the parametric approach, it was demonstrated that the higher the PAE level, the smaller the entire brain, the lower the IQ. Several cortical and subcortical ROIs also exhibited a negative correlation between the PAE level and ROI volume. Furthermore, our data showed that the PAE effect on the brain could not be interpreted by the PAE effect on general physical growth until the young adult age. This study provides valuable insight into specific effects of PAE on human brain and suggests important implications for future studies in this field.

Memory and brain volume in adults prenatally exposed to alcohol.

The impact of prenatal alcohol exposure on memory and brain development was investigated in 92 African-American, young adults who were first identified in the prenatal period. Three groups (Control, n=26; Alcohol-related Neurodevelopmental Disorder, n=36; and Dysmorphic, n=30) were imaged using structural MRI with brain volume calculated for multiple regions of interest. Memory was measured using the Verbal Selective Reminding Memory Test and its nonverbal counterpart, the Nonverbal Selective Reminding Memory Test, which each yielding measures of learning and recall. For both Verbal and Nonverbal Recall and Slope, linear trends were observed demonstrating a spectrum of deficits associated with prenatal alcohol exposure. Dysmorphic individuals performed significantly poorer than unexposed controls on 5 of 6 memory outcomes. Alcohol-exposed individuals demonstrated significantly lower total brain volume than controls, as well as lower volume in a number of specific regions including hippocampus. Mediation analyses indicated that memory performance associated with effects of prenatal alcohol exposure was mediated from dysmorphic severity through hippocampal volume, particularly right hippocampus. These results indicate that the association between the physical effects of prenatal alcohol exposure and deficits in memory are mediated by volumetric reduction in specific brain regions.

Numerical magnitude modulates temporal comparison: an ERP study.

Time is believed to be a part of the generalized magnitude system just like space and quantity. Previous research suggests that time perception can be affected by magnitude in some non-temporal dimensions. Here we address two questions. First, could the influence be caused by an abstract magnitude component without perceptual variables? Second, what are the underlying mechanisms of the influence? Participants compared a pair of durations defined by two Arabic digits in a hundreds of milliseconds range. They performed more accurately when the shorter durations were defined by lower numeric value digits (small digits) and the longer durations were defined by higher value digits (large digits) than they did in the reversed condition. Event-Related Potential (ERP) results showed that the CNVs corresponding to the first duration (CNV1), to the second duration (CNV2) and the N1 were all enhanced when durations marked by small digits than that marked by large ones. Combining the electrophysiological data with the behavioral results, we suggest that digits can modulate performance of temporal comparison at the relatively early stage of perceptual processing. One possible explanation of the current results is that selective temporal attention and subsequent expectation may be involved in this modulation.

Masked smoking-related images modulate brain activity in smokers.

The questions of whether and how indiscriminate drug-related stimuli could influence drug-users are important to our understanding of addictive behavior, but the answers are still inconclusive. In the present preliminary functional magnetic resonance imaging study using a backward masking paradigm, the effect of indiscriminate smoking-related stimuli on 10 smokers and 10 nonsmokers was examined. The BOLD response showed a significant reduction (P = 0.001) in the right amygdala of smokers when they viewed but did not perceive masked smoking-related stimuli, while no significant differences were found in the nonsmoker group. More voxels in anterior cingulate cortex were negatively correlated with the amygdala during the masked smoking-related picture condition in smokers but not in nonsmokers, whereas more positively correlated voxels were observed during the masked neutral condition. The BOLD response in drug-users indicates the amygdala responds to drug-related stimuli that are below the perceptual threshold. The functional connectivity data suggest a functional interaction between the amygdala and the anterior cingulate cortex when drug users view 33 ms back-masked drug-related stimuli. This observation suggests that the amygdala plays an important role in the indiscriminate drug-related cue process.

Larger stimuli are judged to last longer.

Representing magnitude information in various dimensions, including space, quantity, and time, is an important function of the human brain. Many previous studies reported that numerical and spatial magnitudes could be mutually influenced through a "mental number line". In this study, we address the question of whether magnitudes in nontemporal dimensions and magnitudes in time are represented independently or not. Observers judged the duration of the stimuli while four types of nontemporal magnitude information, including number of dots, size of open squares, luminance of solid squares, and numeric value of digits, were manipulated in Stroop-like paradigms. Results revealed that stimuli with larger magnitudes in these nontemporal dimensions were judged to be temporally longer. This observation supports the idea that magnitudes in temporal and nontemporal dimensions are not independent and implies the existence of generalized and abstract components in the magnitude representations.

Binding of verbal and spatial information in human working memory involves large-scale neural synchronization at theta frequency.

Whether neural synchronization is engaged in binding of verbal and spatial information in working memory remains unclear. The present study analyzed oscillatory power and phase synchronization of electroencephalography (EEG) recorded from subjects performing a working memory task. Subjects were required to maintain both verbal (letters) and spatial (locations) information of visual stimuli while the verbal and spatial information were either bound or separate. We found that frontal theta power, and large-scale theta phase synchronization between bilateral frontal regions and between the left frontal and right temporal-parietal regions were greater for maintaining bound relative to separate information. However, the same effects were not observed in the gamma band. These results suggest that working memory binding involves large-scale neural synchronization at the theta band.

The effect of visuospatial attentional load on the processing of irrelevant acoustic distractors.

This work investigated the role of cognitive control functions in selective attention when task-relevant and -irrelevant stimuli come from different sensory modalities. We parametrically manipulated the load of an attentive tracking task and investigated its effect on irrelevant acoustic change-related processing. While subjects were performing the visual attentive tracking task, event-related potentials (ERPs) were recorded for frequent standard tones and rare deviant tones presented as auditory distractors. The deviant tones elicited two change-related ERP components: the mismatch negativity (MMN) and the P3a. The amplitude of the MMN, which indexes the early detection of irregular changes, increased with increasing attentional load, whereas the subsequent P3a component, which indicates the involuntary orienting of attention to deviants, was significant only in the lowest load condition. These findings suggest that active exclusion of the early detection process of irrelevant acoustic changes depends on available resources of cognitive control, whereas the late involuntary orienting of attention to deviants can be passively suppressed by high demand on central attentional resources. The present study thus reveals opposing visual attentional load effects at different temporal and functional stages in the rejection of deviant auditory distractors and provides a new perspective on the resolution of the long-standing early versus late attention selection debate.

fMRI revealed neural substrate for reversible working memory dysfunction in subclinical hypothyroidism.

Cognitive impairments have been found in thyroid hormone-related diseases (e.g. hyperthyroidism and hypothyroidism) for a long time. However, whether and how subclinical hypothyroidism (SCH) causes any deficits in brain functions, and whether a hormone-replacement treatment is necessary for SCH patients, still remain controversial subjects. In the present study, functional MRI (fMRI) was used to measure brain functions by asking euthyroid subjects, hyperthyroid patients and SCH patients to perform the widely used digit n-back working memory task. After having been treated with l-thyroxine for approximately 6 months, the SCH patients were asked to do the same fMRI experiment. The hypothyroid and SCH patients scored significantly lower in the 2-back task than either the hyperthyroid patients or the euthyroid subjects (P < 0.012). The fMRI showed that a common frontoparietal network, including bilateral middle/inferior frontal gyri (M/IFG), bilateral dorsolateral prefrontal cortex (DLPFC), bilateral premotor areas (PreMA), the supplementary motor area/anterior cingulate cortex (SMA/ACC) and bilateral parietal areas (PA), was activated by the n-back task in all the subjects. Further quantitative analysis showed that the load effect of blood oxygen level-dependent (BOLD) response appeared in all the five regions of interest (ROIs) in the euthyroid and hyperthyroid subjects. In the pre-treatment SCH patients, however, the load effect of BOLD response was only found in the PA and PreMA, but not in other frontal cortex ROIs [general linear model (GLM), F < 2.6, P > 0.1]. After an approximately 6 month treatment with LT4, the SCH patients exhibited the same load effects in all five ROIs as the euthyroid subjects (GLM, F > 6, P < 0.05) along with an improvement of performance in n-back task. These results suggest that working memory (but not other memory functions) is impaired in SCH patients, mainly as far as disorders of the frontoparietal network were concerned. Both the memory performance and frontal executive functions were improved after an l-thyroxine-replacement treatment.