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1.  Asymmetry of Subinsular Anisotropy by in vivo Diffusion Tensor Imaging 
Human brain mapping  2003;20(2):82-90.
The cortical regions specialized in speech–language exhibit a left–right asymmetry, e.g., a larger cortical size in the left auditory cortex and Wernicke's area. The possibility of developmental asymmetry in axonal fibers interconnecting speech–language cortical areas can be investigated by in vivo diffusion tensor imaging. Fifteen right-handed native English speakers showed a markedly significant asymmetry (P < 0.0005) in the relative anisotropy of water diffusion in the subinsular white matter, greater on the left. Additionally, the first principal diffusivity was greater and the second and third principal diffusivities were smaller on the left than right side. These results suggest the subinsular axonal structures developed differently between the left and right sides. A possible association between the hemispheric specialization in language and speech and the subinsular axonal fiber development is discussed.
doi:10.1002/hbm.10130
PMCID: PMC3595070  PMID: 14505334
speech; language; symmetry; left-right
2.  Tagging cortical networks in emotion: a topographical analysis 
Human brain mapping  2011;33(12):2920-2931.
Viewing emotional pictures is associated with heightened perception and attention, indexed by a relative increase in visual cortical activity. Visual cortical modulation by emotion is hypothesized to reflect re-entrant connectivity originating in higher-order cortical and/or limbic structures. The present study used dense-array electroencephalography and individual brain anatomy to investigate functional coupling between the visual cortex and other cortical areas during affective picture viewing. Participants viewed pleasant, neutral, and unpleasant pictures that flickered at a rate of 10 Hz to evoke steady-state visual evoked potentials (ssVEPs) in the EEG. The spectral power of ssVEPs was quantified using Fourier transform, and cortical sources were estimated using beamformer spatial filters based on individual structural magnetic resonance images. In addition to lower-tier visual cortex, a network of occipito-temporal and parietal (bilateral precuneus, inferior parietal lobules) structures showed enhanced ssVEP power when participants viewed emotional (either pleasant or unpleasant), compared to neutral pictures. Functional coupling during emotional processing was enhanced between the bilateral occipital poles and a network of temporal (left middle/inferior temporal gyrus), parietal (bilateral parietal lobules), and frontal (left middle/inferior frontal gyrus) structures. These results converge with findings from hemodynamic analyses of emotional picture viewing and suggest that viewing emotionally engaging stimuli is associated with the formation of functional links between visual cortex and the cortical regions underlying attention modulation and preparation for action.
doi:10.1002/hbm.21413
PMCID: PMC3588163  PMID: 21954087
Dense-Array EEG; Emotion; Motivation; Arousal; Picture perception
3.  Physiological Noise Reduction Using Volumetric Functional Magnetic Resonance Inverse Imaging 
Human brain mapping  2011;33(12):2815-2830.
Physiological noise arising from a variety of sources can significantly degrade the detection of task-related activity in BOLD-contrast fMRI experiments. If whole head spatial coverage is desired, effective suppression of oscillatory physiological noise from cardiac and respiratory fluctuations is quite difficult without external monitoring, since traditional EPI acquisition methods cannot sample the signal rapidly enough to satisfy the Nyquist sampling theorem, leading to temporal aliasing of noise. Using a combination of high speed magnetic resonance inverse imaging (InI) and digital filtering, we demonstrate that it is possible to suppress cardiac and respiratory noise without auxiliary monitoring, while achieving whole head spatial coverage and reasonable spatial resolution. Our systematic study of the effects of different moving average (MA) digital filters demonstrates that a MA filter with a 2 s window can effectively reduce the variance in the hemodynamic baseline signal, thereby achieving 57-58% improvements in peak z-statistic values compared to unfiltered InI or spatially smoothed EPI data (FWHM =8.6 mm). In conclusion, the high temporal sampling rates achievable with InI permit significant reductions in physiological noise using standard temporal filtering techniques that result in significant improvements in hemodynamic response estimation.
doi:10.1002/hbm.21403
PMCID: PMC3586826  PMID: 21954026
event-related; inverse imaging; InI; visual; MRI; fMRI; neuroimaging; inverse solution
4.  Comparison of the neural correlates of retrieval success in tests of cued recall and recognition memory 
Human Brain Mapping  2011;33(3):523-533.
The neural correlates of successful retrieval on tests of word stem recall and recognition memory were compared. In the recall test, subjects viewed word stems, half of which were associated with studied items and half with unstudied items, and for each stem attempted to recall a corresponding study word. In the recognition test, old/new judgments were made on old and new words. The neural correlates of successful retrieval were identified by contrasting activity elicited by correctly endorsed test items. Old > new effects common to the two tasks were found in medial and lateral parietal, and right entorhinal cortex. Common new > old effects were identified in medial and left frontal cortex, and left anterior intra-parietal sulcus. Greater old > new effects were evident for cued recall in inferior parietal regions abutting those demonstrating common effects, whereas larger new > old effects were found for recall in left frontal cortex and the anterior cingulate. New > old effects were also found for the recall task in right lateral anterior prefrontal cortex, where they were accompanied by old > new effects during recognition. It is concluded that successful recall and recognition are associated with enhanced activity in a common set of recollection-sensitive parietal regions, and that the greater activation in these regions during recall reflects the greater dependence of that task on recollection. Larger new > old effects during recall are interpreted as reflections of the greater opportunity for iterative retrieval attempts when retrieval cues are partial rather than copy cues.
doi:10.1002/hbm.21229
PMCID: PMC3129402  PMID: 21455941
episodic memory; recognition memory; cued recall; fMRI; parietal cortex; recollection
5.  Spontaneous and visually-driven high-frequency oscillations in the occipital cortex: Intracranial recording in epileptic patients 
Human Brain Mapping  2011;33(3):569-583.
SUMMARY
High-frequency oscillations (HFOs) at ≧80 Hz of nonepileptic nature spontaneously emerge from human cerebral cortex. In 10 patients with extra-occipital lobe epilepsy, we compared the spectral-spatial characteristics of HFOs spontaneously arising from the nonepileptic occipital cortex with those of HFOs driven by a visual task as well as epileptogenic HFOs arising from the extra-occipital seizure focus. We identified spontaneous HFOs at ≧80 Hz with a mean duration of 330 msec intermittently emerging from the occipital cortex during interictal slow-wave sleep. The spectral frequency band of spontaneous occipital HFOs was similar to that of visually-driven HFOs. Spontaneous occipital HFOs were spatially sparse and confined to smaller areas, whereas visually-driven HFOs involved the larger areas including the more rostral sites. Neither spectral frequency band nor amplitude of spontaneous occipital HFOs significantly differed from those of epileptogenic HFOs. Spontaneous occipital HFOs were strongly locked to the phase of delta activity, but the strength of delta-phase coupling decayed from 1 to 3 Hz. Conversely, epileptogenic extra-occipital HFOs were locked to the phase of delta activity about equally in the range from 1 to 3 Hz. The occipital cortex spontaneously generates physiological HFOs which may stand out on electrocorticography traces as prominently as pathological HFOs arising from elsewhere; this observation should be taken into consideration during presurgical evaluation. Coupling of spontaneous delta and HFOs may increase the understanding of significance of delta-oscillations during slow-wave sleep. Further studies are warranted to determine whether delta-phase coupling distinguishes physiological from pathological HFOs or simply differs across anatomical locations.
doi:10.1002/hbm.21233
PMCID: PMC3220781  PMID: 21432945
epilepsy surgery; fast ripples; in-vivo animation of event-related gamma-oscillations; electroencephalography (EEG); memory consolidation; perceptual visual learning; slow-wave sleep
6.  Depression of Cortical Activity in Humans by Mild Hypercapnia 
Human brain mapping  2011;33(3):715-726.
The effects of neural activity on cerebral hemodynamics underlie human brain imaging with functional magnetic resonance imaging and positron emission tomography. However, the threshold and characteristics of the converse effects, wherein the cerebral hemodynamic and metabolic milieu influence neural activity, remain unclear. We tested whether mild hypercapnia (5% CO2) decreases the magnetoencephalogram response to auditory pattern recognition and visual semantic tasks. Hypercapnia induced statistically significant decreases in event-related fields without affecting behavioral performance. Decreases were observed in early sensory components in both auditory and visual modalities as well as later cognitive components related to memory and language. Effects were distributed across cortical regions. Decreases were comparable in evoked versus spontaneous spectral power. Hypercapnia is commonly used with hemodynamic models to calibrate the blood oxygenation level-dependent response. Modifying model assumptions to incorporate the current findings produce a modest but measurable decrease in the estimated cerebral metabolic rate for oxygen change with activation. Because under normal conditions, low cerebral pH would arise when bloodflow is unable to keep pace with neuronal activity, the cortical depression observed here may reflect a homeostatic mechanism by which neuronal activity is adjusted to a level that can be sustained by available bloodflow. Animal studies suggest that these effects may be mediated by pH-modulating presynaptic adenosine receptors. Although the data is not clear, comparable changes in cortical pH to those induced here may occur during sleep apnea, sleep, and exercise. If so, these results suggest that such activities may in turn have generalized depressive effects on cortical activity.
doi:10.1002/hbm.21242
PMCID: PMC3558280  PMID: 21500313
cerebral blood flow; cerebral metabolic rate for oxygen; blood oxygenation level-dependent response; functional magnetic resonance imaging; magnetoencephalography; temporal lobe; prefrontal cortex; occipital lobe; carbon dioxide; arterial spin labeling
7.  Prefrontal D2-Receptor Stimulation Mediates Flexible Adaptation of Economic Preference Hierarchies 
Human brain mapping  2011;34(1):226-232.
Advantageous economic decision making requires flexible adaptation of gain-based and loss-based preference hierarchies. However, where the neuronal blueprints for economic preference hierarchies are kept and how they may be adapted remains largely unclear. Phasic cortical dopamine release likely mediates flexible adaptation of neuronal representations. In this PET study, cortical-binding potential (BP) for the D2-dopamine receptor ligand [11C]FLB 457 was examined in healthy participants during multiple sessions of a probabilistic four-choice financial decision-making task with two behavioral variants. In the changing-gains/constant-losses variant, the implicit gain-based preference hierarchy was unceasingly changing, whereas the implicit loss-based preference hierarchy was constant. In the constant-gains/changing-losses variant, it was the other way around. These variants served as paradigms, respectively, contrasting flexible adaptation versus maintenance of loss-based and gain-based preference hierarchies. We observed that in comparison with the constant-gains/changing-losses variant, the changing-gains/constant-losses variant was associated with a decreased D2-dopamine receptor-BP in the right lateral frontopolar cortex. In other words, lateral frontopolar D2-dopamine receptor stimulation was specifically increased during continuous adaptation of mental representations of gain-based preference hierarchies. This finding provides direct evidence for the existence of a neuronal blueprint of gain-based decision-making in the lateral frontopolar cortex and a crucial role of local dopamine in the flexible adaptation of mental concepts of future behavior.
doi:10.1002/hbm.21425
PMCID: PMC3521779  PMID: 22020993 CAMSID: cams2371
dopamine; feedback-learning; frontopolar; FLB; imaging; gambling
8.  Reliability of fMRI Associative Encoding Memory Paradigm in Non-Demented Elderly Adults 
Human brain mapping  2011;32(12):2027-2044.
Functional MRI holds significant potential to aid in the development of early interventions to improve memory function, and to assess longitudinal change in memory systems in aging and early Alzheimer's disease. However, the test-retest reliability of hippocampal activation and of “beneficial” deactivation in the precuneus has yet to be fully established during memory encoding tasks in older subjects. Using a mixed block and event-related face-name associative encoding paradigm, the reliability of hippocampal activation and default network deactivation was assessed over a four-to-six week inter-scan interval in 27 older individuals who were cognitively normal (Clinical Dementia Rating Scale= 0; n=18) or very mildly impaired (CDR=0.5; n=9). Reliability was assessed in whole brain maps and regions-of-interest using both a full task paradigm of six functional runs as well as an abbreviated paradigm of the first two functional runs, which would be advantageous for use in clinical trials. We found reliable hippocampal signal response across both block and event-related designs in the right hippocampus. Comparable reliability in hippocampal activation was found in the full and the abbreviated paradigm. Similar reliability in hippocampal activation was observed across both CDR groups overall, but the CDR 0.5 group was more variable in left hippocampal activity. Task-related deactivation in the precuneus demonstrated much greater variability than hippocampal activation in all analyses. Overall, these results are encouraging for the utility of fMRI in “Proof of Concept” clinical trials investigating the efficacy of potentially therapeutic agents for treatment of age-related memory changes, cognitive impairment, and early Alzheimer's disease.
doi:10.1002/hbm.21166
PMCID: PMC3551453  PMID: 21259385
test-retest; hippocampus; precuneus; reliability; mild cognitive impairment; aging
9.  Adaptive Control of the False Discovery Rate in Voxel-Based Morphometry 
Human brain mapping  2009;30(7):2304-2311.
Voxel-based morphometry (VBM) is widely used as a high-resolution approach to understanding the relationship between anatomical structures and variables of interest. Controlling for the false discovery rate (FDR) is an attractive choice for thresholding the resulting statistical maps and has been commonly used in fMRI studies. However, we caution against the use of nonadaptive FDR control procedures, such as the most commonly used Benjamini–Hochberg procedure (B-H), in VBM analyses. This is because, in VBM analyses, specific risk factors may be associated with volume change in a global, rather than local, manner, which means the proportion of truly associated voxels among all voxels is large. In such a case, the achieved FDR obtained by nonadaptive procedures can be substantially lower than the nominal, or controlled, level. Such conservatism deprives researchers of power for detecting true associations. In this article, we advocate for the use of adaptive FDR control in VBM-type analyses. Specifically, we examine two representative adaptive procedures: the two-stage step-up procedure by Benjamini, Krieger and Yekutieli ([2006]: Biometrika 93:491-507) and the procedure of Storey and Tibshirani ([2003]: Proc Natl Acad Sci USA 100:9440-9445). We demonstrate mathematically, with simulations, and with a data example that these procedures provide improved performance over the B-H procedure.
doi:10.1002/hbm.20669
PMCID: PMC3530395  PMID: 19034901
voxel-based morphometry; false discovery rate; Benjamini and Hochberg procedure
10.  Cortical network differences in the sighted versus early blind for recognition of human-produced action sounds 
Human brain mapping  2011;32(12):2241-2255.
Both sighted and blind individuals can readily interpret meaning behind everyday real-world sounds. In sighted listeners, we previously reported that regions along the bilateral posterior superior temporal sulci (pSTS) and middle temporal gyri (pMTG) are preferentially activated when presented with recognizable action sounds. These regions have generally been hypothesized to represent primary loci for complex motion processing, including visual biological motion processing and audio-visual integration. However, it remained unclear whether, or to what degree, life-long visual experience might impact functions related to hearing perception or memory of sound-source actions. Using functional magnetic resonance imaging (fMRI), we compared brain regions activated in congenitally blind versus sighted listeners in response to hearing a wide range of recognizable human-produced action sounds (excluding vocalizations) versus unrecognized, backward-played versions of those sounds. Here we show that recognized human action sounds commonly evoked activity in both groups along most of the left pSTS/pMTG complex, though with relatively greater activity in the right pSTS/pMTG by the blind group. These results indicate that portions of the postero-lateral temporal cortices contain domain-specific hubs for biological and/or complex motion processing independent of sensory-modality experience. Contrasting the two groups, the sighted listeners preferentially activated bilateral parietal plus medial and lateral frontal networks, while the blind listeners preferentially activated left anterior insula plus bilateral anterior calcarine and medial occipital regions, including what would otherwise have been visual-related cortex. These global-level network differences suggest that blind and sighted listeners may preferentially use different memory retrieval strategies when attempting to recognize action sounds.
doi:10.1002/hbm.21185
PMCID: PMC3517890  PMID: 21305666
Hearing perception; episodic memory; mirror-neuron systems; cortical plasticity; fMRI
11.  Identification of Human Gustatory Cortex by Activation Likelihood Estimation 
Human brain mapping  2011;32(12):2256-2266.
Over the last two decades, neuroimaging methods have identified a variety of taste-responsive brain regions. Their precise location, however, remains in dispute. For example, taste stimulation activates areas throughout the insula and overlying operculum, but identification of subregions has been inconsistent. Furthermore, literature reviews and summaries of gustatory brain activations tend to reiterate rather than resolve this ambiguity. Here we used a new meta-analytic method [activation likelihood estimation (ALE)] to obtain a probability map of the location of gustatory brain activation across fourteen studies. The map of activation likelihood values can also serve as a source of independent coordinates for future region-of-interest analyses. We observed significant cortical activation probabilities in: bilateral anterior insula and overlying frontal operculum, bilateral mid dorsal insula and overlying Rolandic operculum, and bilateral posterior insula/parietal operculum/postcentral gyrus, left lateral orbitofrontal cortex (OFC), right medial OFC, pregenual anterior cingulate cortex (prACC) and right mediodorsal thalamus. This analysis confirms the involvement of multiple cortical areas within insula and overlying operculum in gustatory processing and provides a functional “taste map” which can be used as an inclusive mask in the data analyses of future studies. In light of this new analysis, we discuss human central processing of gustatory stimuli and identify topics where increased research effort is warranted.
doi:10.1002/hbm.21188
PMCID: PMC3123671  PMID: 21305668
activation likelihood estimation; functional brain imaging; fMRI; gustation; taste; PET
12.  What’s the Story? The Tale of Reading Fluency Told at Speed 
Human brain mapping  2011;33(11):2572-2585.
Fluent readers process written text rapidly and accurately, and comprehend what they read. Historically, reading fluency has been modeled as the product of discrete skills such as single word decoding. More recent conceptualizations emphasize that fluent reading is the product of competency in, and the coordination of, multiple cognitive sub-skills (a multi-componential view). In this study, we examined how the pattern of activation in core reading regions changes as the ability to read fluently is manipulated through reading speed. We evaluated 13 right-handed adults with a novel fMRI task assessing fluent sentence reading and lower-order letter reading at each participant’s normal fluent reading speed, as well as constrained (slowed) and accelerated reading speeds. Comparing fluent reading conditions with rest revealed regions including bilateral occipito-fusiform, left middle temporal, and inferior frontal gyral clusters across reading speeds. The selectivity of these regions’ responses to fluent sentence reading was shown by comparison with the letter reading task. Region of interest analyses showed that at constrained and accelerated speeds these regions responded significantly more to fluent sentence reading. Critically, as reading speed increased, activation increased in a single reading-related region: occipital/fusiform cortex (left > right). These results demonstrate that while brain regions engaged in reading respond selectively during fluent reading, these regions respond differently as the ability to read fluently is manipulated. Implications for our understanding of reading fluency, reading development, and reading disorders are discussed.
doi:10.1002/hbm.21384
PMCID: PMC3499039  PMID: 21954000
reading; language; fluency; fluent; fMRI; event-related
13.  Biphasic Hemodynamic Responses Influence Deactivation and May Mask Activation in Block-Design fMRI Paradigms 
Human brain mapping  2008;29(4):385-399.
A previous block-design fMRI study revealed deactivation in the hippocampus in the transverse patterning task, specifically designed, on the basis of lesion literature, to engage hippocampal information processing. In the current study, a mixed block/event-related design was used to determine the temporal nature of the signal change leading to the seemingly paradoxical deactivation. All positive activations in the hippocampal-dependent condition, relative to a closely matched control task, were seen to result from positive BOLD transients in the typical 4–7 s poststimulus time range. However, most deactivations, including in the hippocampus and in other “default mode” regions commonly deactivated in cognitive tasks, were attributable to enhanced negative transient signals in a later time range, 10–12 s. This late hemodynamic transient was most pronounced in medial prefrontal cortex. In some regions, the hippocampal-dependent condition enhanced both the early positive and late negative transients to approximately the same degree, resulting in no significant signal change when block analysis is used, despite very different event-related responses. These results imply that delayed negative transients can play a role in determining the presence and sign of brain activation in block-design studies, in which case an event-related analysis can be more sensitive than a block analysis, even if the different conditions occur within blocks. In this case, default mode deactivations are timelocked to stimulus presentation as much as positive activations are, but in a later time range, suggesting a specific role of negative transient signals in task performance.
doi:10.1002/hbm.20391
PMCID: PMC3496427  PMID: 17450579
default mode; negative BOLD; undershoot; event-related; CBV; CBF; CMRO2; hippocampus; transverse patterning
14.  Topographical relationships between arcuate fasciculus connectivity and cortical thickness 
Human brain mapping  2010;32(11):1788-1801.
The arcuate fasciculus (AF) connects cortical regions important in language processing, but how fiber coherence and organization relates to gray matter macrostructure remains uncharacterized. We used high-resolution structural and 30-direction diffusion imaging data from 36 healthy adults (24 male/12 female; mean age: 30.5±9.8 years) to establish the relationships between AF microstructure and regional variations in cortical gray matter within language networks. Cortical pattern matching algorithms were used to measure gray matter thickness at high spatial density, and a validated diffusion tractography method was used to reconstruct the AF in the left and right hemisphere of each subject. Relationships between imaging measures and neuropsychological scores of verbal fluency were additionally assessed. Results revealed positive and highly topographical associations between arcuate fractional anisotropy and cortical thickness within anterior and posterior language regions and surrounding cortices, more prominently in the left hemisphere. These regional cortical thickness/fractional anisotropy relationships were primarily attributable to variations in radial diffusivity. Associations between cortical thickness and verbal fluency were observed in perisylvian language-related regions. Language scores associated with left hemisphere AF axial diffusivity, but not with AF fractional anisotropy or radial diffusivity. These findings thus suggest that particular components of white matter microstructure and regional increases in cortical thickness benefit aspects of language processing. Further, the topographical relationships between independent measures of white matter and gray matter integrity suggest that rich developmental or environmental interactions influence brain structure and function where the presence and strength of such associations may elucidate pathophysiological processes influencing language systems.
doi:10.1002/hbm.21147
PMCID: PMC3071430  PMID: 20886580
Diffusion Tensor Imaging; Magnetic Resonance Imaging; white matter; gray matter; language; neuroanatomy; tractography; superior longitudinal fasciculus; fractional anisotropy
15.  Altered Default Mode Network Connectivity in Alzheimer’s Disease--A Resting Functional MRI and Bayesian Network Study 
Human brain mapping  2011;32(11):1868-1881.
A number of functional magnetic resonance imaging (fMRI) studies reported the existence of default mode network (DMN) and its disruption due to the presence of a disease such as Alzheimer’s disease (AD). In this current investigation, firstly, we used the independent component analysis (ICA) technique to confirm the DMN difference between patients with AD and normal control (NC) reported in previous studies. Consistent with previous studies, the decreased resting-state functional connectivity of DMN in AD was identified in posterior cingulated cortex (PCC), medial prefrontal cortex (MPFC), inferior parietal cortex (IPC), inferior temporal cortex (ITC) and hippocampus (HC). Moreover, we introduced Bayesian Network (BN) to study the effective connectivity of DMN and the difference between AD and NC. Compared the DMN effective connectivity in AD to the one in NC using a non-parametric random permutation test, we found that connections from left HC to left IPC, left ITC to right HC, right HC to left IPC, to MPFC and to PCC were all lost. In addition, in AD group, the connection directions between right HC and left HC, between left HC and left ITC, and between right IPC and right ITC were opposite to those in NC group. The connections of right HC to other regions, except left HC, within the BN were all statistically in-distinguishable from 0, suggesting an increased right hippocampal pathological and functional burden in AD. The altered effective connectivity in patients with AD may reveal more characteristics of the disease and may serve as a potential biomarker.
doi:10.1002/hbm.21153
PMCID: PMC3208821  PMID: 21259382
biomarker; effective connectivity; functional connectivity; resting state; fMRI
16.  Anxiety positive subjects show altered processing in the anterior insula during anticipation of negative stimuli 
Human brain mapping  2010;32(11):1836-1846.
Prior neuroimaging studies support the hypothesis that anticipation, an important component of anxiety, may be mediated by activation within the insular and medial prefrontal cortices including the anterior cingulate cortex. However, there is an insufficient understanding of how affective anticipation differs across anxiety groups in emotional brain loci and networks. We examined 14 anxiety positive (AP) and 14 anxiety normative (AN) individuals completing an affective picture anticipation task during functional magnetic resonance imaging (fMRI). Brain activation was examined across groups for cued anticipation (to aversive or pleasant stimuli). Both groups showed greater activation in the bilateral anterior insula during cued differential anticipation (i.e., aversive vs. pleasant) and activation on the right was significantly higher in AP compared to AN subjects. Functional connectivity showed that the left anterior insula was involved in a similar network during pleasant anticipation in both groups. The left anterior insula during aversive and the right anterior insula during all anticipation conditions co-activated with a cortical network consisting of frontal and parietal lobes in the AP group to a greater degree. These results are consistent with the hypothesis that anxiety is related to greater anticipatory reactivity in the brain and that there may be functional asymmetries in the brain that interact with psychiatric traits.
doi:10.1002/hbm.21154
PMCID: PMC3215249  PMID: 21181800
17.  Functional Connectivity in Mild Traumatic Brain Injury 
Human brain mapping  2011;32(11):1825-1835.
Objectives
Research suggests that the majority of mild traumatic brain injury (mTBI) patients exhibit both cognitive and emotional dysfunction within the first weeks of injury, followed by symptom resolution 3–6 months post-injury. The neuronal correlates of said dysfunction are difficult to detect with standard clinical neuroimaging, complicating differential diagnosis and early identification of patients who may not recover. The current study examined whether resting state functional magnetic resonance imaging (FMRI) provides objective markers of injury and predicts cognitive, emotional and somatic complaints in mTBI patients semi-acutely (< 3 weeks post-injury) and in late recovery (3–5 month) phases.
Methods
Twenty seven semi-acute mTBI patients and 26 gender, age and education matched controls were studied. Fifteen out of 27 patients returned for a follow-up visit 3–5 months post-injury. The main dependent variables were spontaneous fluctuations (temporal correlation) in the default-mode (DMN) and fronto-parietal task-related (TRN) networks as measured by FMRI.
Results
Significant differences in self-reported cognitive, emotional and somatic complaints were observed (all p < .05), despite normal clinical (T1 and T2) imaging and neuropsychological testing results. Mild TBI patients demonstrated decreased functional connectivity within the DMN and hyper-connectivity between the DMN and lateral prefrontal cortex. Measures of functional connectivity exhibited high levels of sensitivity and specificity for patient classification and predicted cognitive complaints in the semi-acute injury stage. However, no changes in functional connectivity were observed across a four month recovery period.
Conclusions
Abnormal connectivity between the DMN and frontal cortex may provide objective biomarkers of mTBI and underlie cognitive impairment.
doi:10.1002/hbm.21151
PMCID: PMC3204375  PMID: 21259381
mild TBI; attention; connectivity; FMRI; DTI
18.  Sex Differences in Neural Responses to Stress and Alcohol Context Cues 
Human brain mapping  2010;32(11):1998-2013.
Stress and alcohol context cues are each associated with alcohol-related behaviors, yet neural responses underlying these processes remain unclear. The present study investigated the neural correlates of stress and alcohol context cue experiences and examined sex differences in these responses. Using functional magnetic resonance imaging, brain responses were examined while 43 right-handed, socially drinking, healthy individuals (23 females) engaged in brief guided imagery of personalized stress, alcohol-cue and neutral-relaxing scenarios. Stress and alcohol-cue exposure increased activity in the cortico-limbic-striatal circuit (p<.01, corrected), encompassing the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), left anterior insula, striatum and visuomotor regions (parietal and occipital lobe, and cerebellum). Activity in the right dorsal striatum increased during stress, while bilateral ventral striatum activity was evident during alcohol-cue exposure. Men displayed greater stress-related activations in the mPFC, rostral ACC, posterior insula, amygdala and hippocampus than women, whereas women showed greater alcohol-cue related activity in the superior and middle frontal gyrus (SFG/MFG) than men. Stress-induced anxiety was positively associated with activity in emotion modulation regions, including the medial OFC, ventromedial PFC, left superior-medial PFC and rostral ACC in men, but in women with activation in the SFG/MFG, regions involved in cognitive processing. Alcohol craving was significantly associated with the striatum (encompassing dorsal and ventral) in men, supporting its involvement in alcohol ‘urge’ in healthy men. These results indicate sex differences in neural processing of stress and alcohol-cue experiences, and have implications for sex-specific vulnerabilities to stress- and alcohol-related psychiatric disorders.
doi:10.1002/hbm.21165
PMCID: PMC3236497  PMID: 21162046
Sex differences; Stress; Alcohol cue; Reward; Brain fMRI; Prefrontal Cortex
19.  The “Task B problem” and other considerations in developmental functional neuroimaging 
Human brain mapping  2010;31(6):852-862.
Functional neuroimaging provides a remarkable tool to allow us to study cognition across the lifespan and in special populations in a safe way. However, experimenters face a number of methodological issues, and these issues are particularly pertinent when imaging children. This brief article discusses assessing task performance, strategies for dealing with group performance differences, controlling for movement, statistical power, proper atlas registration, and data analysis strategies. In addition, there will be discussion of two other topics that have important implications for interpreting fMRI data: the question of whether functional neuroanatomical differences between adults and children are the consequence of putative developmental neurovascular differences, and the issue of interpreting negative blood oxygenation-level dependent (BOLD) signal change.
doi:10.1002/hbm.21036
PMCID: PMC3468298  PMID: 20496376
fMRI; methods; negative BOLD; group differences
20.  Distinct Functional Networks Associated with Improvement of Affective Symptoms and Cognitive Function During Citalopram Treatment in Geriatric Depression 
Human brain mapping  2010;32(10):1677-1691.
Variability in the affective and cognitive symptom response to antidepressant treatment has been observed in geriatric depression. The underlying neural circuitry is poorly understood. The current study evaluated the cerebral glucose metabolic effects of citalopram treatment and applied multivariate, functional connectivity analyses to identify brain networks associated with improvements in affective symptoms and cognitive function. Sixteen geriatric depressed patients underwent resting Positron Emission Tomography (PET) studies of cerebral glucose metabolism and assessment of affective symptoms and cognitive function before and after eight weeks of selective serotonin reuptake inhibitor treatment (citalopram). Voxel-wise analyses of the normalized glucose metabolic data showed decreased cerebral metabolism during citalopram treatment in the anterior cingulate gyrus, middle temporal gyrus, precuneus, amygdala, and parahippocampal gyrus. Increased metabolism was observed in the putamen, occipital cortex and cerebellum. Functional connectivity analyses revealed two networks which were uniquely associated with improvement of affective symptoms and cognitive function during treatment. A subcortical-limbic-frontal network was associated with improvement in affect (depression and anxiety), while a medial temporal-parietal-frontal network was associated with improvement in cognition (immediate verbal learning/memory and verbal fluency). The regions that comprise the cognitive network overlap with the regions that are affected in Alzheimer’s dementia. Thus, alterations in specific brain networks associated with improvement of affective symptoms and cognitive function are observed during citalopram treatment in geriatric depression.
doi:10.1002/hbm.21135
PMCID: PMC3021765  PMID: 20886575
selective serotonin reuptake inhibitors; citalopram; serotonin; Positron Emission Tomography (PET); glucose metabolism; functional connectivity; partial least squares (PLS); depression; aging
21.  Modulation of Steady State Functional Connectivity in the Default Mode and Working Memory Networks By Cognitive Load 
Human brain mapping  2010;32(10):1649-1659.
Interregional correlations between blood oxygen level dependent (BOLD) magnetic resonance imaging (fMRI) signals in the resting state have been interpreted as measures of connectivity across the brain. Here we investigate whether such connectivity in the working memory and default mode networks is modulated by changes in cognitive load. Functional connectivity was measured in a steady-state verbal identity N-back task for three different conditions (N = 1, 2, and 3) as well as in the resting state. We found that as cognitive load increases, the functional connectivity within both the working memory the default mode network increases. In order to test whether functional connectivity between the working memory and the default mode networks changed, we constructed maps of functional connectivity to the working memory network as a whole and found that increasingly negative correlations emerged in a dorsal region of the posterior cingulate cortex. These results provide further evidence that low frequency fluctuations in BOLD signals reflect variations in neural activity and suggests interaction between the default mode network and other cognitive networks.
doi:10.1002/hbm.21138
PMCID: PMC3116941  PMID: 21077136
fMRI; functional connectivity; working memory; default mode
22.  Visual Phonetic Processing Localized Using Speech and Non-Speech Face Gestures in Video and Point-Light Displays 
Human brain mapping  2010;32(10):1660-1676.
The talking face affords multiple types of information. To isolate cortical sites with responsibility for integrating linguistically relevant visual speech cues, speech and non-speech face gestures were presented in natural video and point-light displays during fMRI scanning at 3.0T. Participants with normal hearing viewed the stimuli and also viewed localizers for the fusiform face area (FFA), the lateral occipital complex (LOC), and the visual motion (V5/MT) regions of interest (ROIs). The FFA, the LOC, and V5/MT were significantly less activated for speech relative to non-speech and control stimuli. Distinct activation of the posterior superior temporal sulcus and the adjacent middle temporal gyrus to speech, independent of media, was obtained in group analyses. Individual analyses showed that speech and non-speech stimuli were associated with adjacent but different activations, with the speech activations more anterior. We suggest that the speech activation area is the temporal visual speech area (TVSA), and that it can be localized with the combination of stimuli used in this study.
doi:10.1002/hbm.21139
PMCID: PMC3120928  PMID: 20853377
visual perception; speech perception; functional magnetic resonance imaging; lipreading; speechreading; phonetics; gestures; temporal lobe; frontal lobe; parietal lobe
23.  Electrocorticographic correlates of cognitive control in a Stroop task 
Human brain mapping  2010;32(10):1580-1591.
SUMMARY
The human brain executes cognitive control, such as selection of relevant information in the presence of competing irrelevant information, and cognitive control is essential for us to yield a series of optimal behaviors in our daily life. The present study assessed electrocorticographic gamma-oscillations elicited by cognitive control in the context of the Stroop color-naming paradigm, with a temporal resolution of 10 msec and spatial resolution of 1 cm. Subjects were instructed to overtly read a color word printed in an incongruent color in the reading task, and to overtly name the ink color of a color word printed in an incongruent color in the Stroop color-naming task. The latter task specifically elicited larger gamma-augmentations in the dorsolateral-premotor, dorsolateral-prefrontal and supplementary motor areas with considerable inter-subject spatial variability. Such Stroop color-naming-specific gamma-augmentations occurred approximately 500 to 200 msec prior to overt responses. Electrical stimulation of the sites showing Stroop color-naming-specific gamma-augmentations resulted in temporary naming impairment more frequently than that of the remaining sites. This study has provided direct evidence that a critical process of cognitive control in the context of Stroop color-naming paradigm consists of recruitment of neurons essential for naming located in variable portions of the dorsolateral premotor and prefrontal areas.
doi:10.1002/hbm.21129
PMCID: PMC3170495  PMID: 20845393
cognitive control; executive function; intracranial recording; local field potentials; in-vivo animation of event-related gamma-oscillations
24.  Face-Likeness and Image Variability Drive Responses in Human Face-Selective Ventral Regions 
Human brain mapping  2011;33(10):2334-2349.
The human ventral visual stream contains regions that respond selectively to faces over objects. However, it is unknown whether responses in these regions correlate with how face-like stimuli appear. Here, we use parameterized face silhouettes to manipulate the perceived face-likeness of stimuli and measure responses in face- and object-selective ventral regions with high-resolution fMRI. We first use “concentric hyper-sphere” (CH) sampling to define face silhouettes at different distances from the prototype face. Observers rate the stimuli as progressively more face-like the closer they are to the prototype face. Paradoxically, responses in both face- and object-selective regions decrease as face-likeness ratings increase. Because CH sampling produces blocks of stimuli whose variability is negatively correlated with face-likeness, this effect may be driven by more adaptation during high face-likeness (low-variability) blocks than during low face-likeness (high-variability) blocks. We tested this hypothesis by measuring responses to matched-variability (MV) blocks of stimuli with similar face-likeness ratings as with CH sampling. Critically, under MV sampling, we find a face-specific effect: responses in face-selective regions gradually increase with perceived face-likeness, but responses in object-selective regions are unchanged. Our studies provide novel evidence that face-selective responses correlate with the perceived face-likeness of stimuli, but this effect is revealed only when image variability is controlled across conditions. Finally, our data show that variability is a powerful factor that drives responses across the ventral stream. This indicates that controlling variability across conditions should be a critical tool in future neuroimaging studies of face and object representation.
doi:10.1002/hbm.21367
PMCID: PMC3404198  PMID: 21823208
face-likeness; variability; face silhouettes; FFA; fMRI

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