Oxygen Level-dependent Functional Magnetic Resonance Research Articles

Impact of Sleep Quality on Amygdala Reactivity, Negative Affect, and Perceived Stress

Research demonstrates a negative impact of sleep disturbance on mood and affect; however, the biological mechanisms mediating these links are poorly understood. Amygdala reactivity to negative stimuli has emerged as one potential pathway. Here, we investigate the influence of self-reported sleep quality on associations between threat-related amygdala reactivity and measures of negative affect and perceived stress. Analyses on data from 299 participants (125 men, 50.5% white, mean [standard deviation] age = 19.6 [1.3] years) who completed the Duke Neurogenetics Study were conducted. Participants completed several self-report measures of negative affect and perceived stress. Threat-related (i.e., angry and fearful facial expressions) amygdala reactivity was assayed using blood oxygen level-dependent functional magnetic resonance imaging. Global sleep quality was assessed using the Pittsburgh Sleep Quality Index. Amygdala reactivity to fearful facial expressions predicted greater depressive symptoms and higher perceived stress in poor (β values = 0.18-1.86, p values < .05) but not good sleepers (β values = -0.13 to -0.01, p values > .05). In sex-specific analyses, men reporting poorer global sleep quality showed a significant association between amygdala reactivity and levels of depression and perceived stress (β values = 0.29-0.44, p values < .05). In contrast, no significant associations were observed in men reporting good global sleep quality or in women, irrespective of sleep quality. This study provides novel evidence that self-reported sleep quality moderates the relationships between amygdala reactivity, negative affect, and perceived stress, particularly among men.

Analysis of occipital lobe activation during functional MRI in patients with open-angle glaucoma and correlation with clinical results

Objective To evaluate the activation of the visual cortex in patients with primary open-angle glaucoma (POAG) and to explore whether the neuronal activity corresponds with retinal nerve fiber layer (RNFL) and cup-to-disc (C/D) values. Methods Twenty-five patients and 25 gender-and age-matched healthy volunteers were studied.Blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-f MRI) and three-dimensional brain volume imaging (3D BRAVO) sequences were obtained using 3 T MR imaging system.A full-screen black-white shift checkerboard was used for visual stimulus during the f MRIexperiment and was performed on each eye of all subjects using a visual-acoustical system.All acquired data were postprocessed and analyzed by statistical parametric mapping (SPM).After analysis,individual activated mapping,intra-group mean activated mapping,and inter-group variant mapping were observed.The voxel number,intensity,and Montreal Neurological Institute (MNI) coordinate of the activated clusters were recorded.The Xjviewer software was utilized to obtain activated voxel numbers in occipital lobe.A Pearson correlated test was performed to test the correlation between the number of activated voxels and RNFL,C/D and Hodapp-Anderson-Parrish (HAP) clinical stage. Results Intra-group mean activated mappings of both patients and volunteers showed obvious activation in bilateral occipital lobes.As compared with healthy volunteers,the POAG patients exhibited statistically significantly decreased activation in bilateral occipital lobes,left hippocampus,and left cerebellum,along with lower mean RNFL[ (71.56±21.54) μm versus (111.88±9.96) μm] and higher C/D values (0.71±0.18 versus 0.36±0.08; tvalue was respectively-10.901 and 11.643,P 0.05). Conclusions f MRI demonstrated differences in visual cortex activation in POAG patients relative to healthy volunteers,suggesting it might be a promising complementary method for diagnosing glaucoma.However,f MRI findings did not correlate with POAG extent,as measured by RNFL and C/ D values.Ophthalmological examination remains to play an important role in the evaluation of openangle glaucoma. Key words: Glaucoma; Magnetic resonance imaging; Photic stimulus

Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans

A corticolimbic circuit including the amygdala and medial prefrontal cortex (mPFC) plays an important role in regulating sensitivity to threat, which is heightened in mood and anxiety disorders. Serotonin is a potent neuromodulator of this circuit; however, specific serotonergic mechanisms mediating these effects are not fully understood. Recent studies have evaluated molecular mechanisms mediating the effects of serotonin signalling on corticolimbic circuit function using a multi-modal neuroimaging strategy incorporating positron emission tomography and blood oxygen level-dependent functional magnetic resonance imaging. This multi-modal neuroimaging strategy can be integrated with additional techniques including imaging genetics and pharmacological challenge paradigms to more clearly understand how serotonin signalling modulates neural pathways underlying sensitivity to threat. Integrating these methodological approaches offers novel opportunities to identify mechanisms through which serotonin signalling contributes to differences in brain function and behaviour, which in turn can illuminate factors that confer risk for illness and inform the development of more effective treatment strategies.

Age‐related differences in working memory deficits during nicotine withdrawal

Nicotine withdrawal is associated with subtle working memory deficits that predict subsequent relapse. We examined the neural substrates underlying these processes in treatment-seeking smokers, and explored the moderating influence of age on abstinence-induced alterations in brain activity and performance. Sixty-three smokers participated in two blood oxygen level-dependent (BOLD) functional magnetic resonance imaging scans while performing a visual N-back task on two separate occasions: smoking as usual and after 24 hours of biochemically confirmed abstinence (order counterbalanced). Abstinence (versus smoking) led to reduced accuracy, slower median correct response time and reduced BOLD signal change in the three a priori regions of interest: medial frontal/cingulate gyrus and right and left dorsolateral prefrontal cortex. Significant age × session effects were found for BOLD signal change in all three regions, as well as for withdrawal and craving; for all measures, abstinence effects were attenuated in smokers aged ≥50 years compared with those <50 years old. These results suggest that abstinence effects on neurocognitive function may be more pronounced for younger smokers, and may indicate a new avenue for research exploring mechanisms underlying age differences in smoking cessation success.

Using Functional Magnetic Resonance Imaging to Determine if Cerebral Hemodynamic Responses to Pain Change Following Thoracic Spine Thrust Manipulation in Healthy Individuals

Case series. To use blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) to determine if supraspinal activation in response to noxious mechanical stimuli varies pre- and post-thrust manipulation to the thoracic spine. Recent studies have demonstrated the effectiveness of thoracic thrust manipulation in reducing pain and improving function in some individuals with neck and shoulder pain. However, the mechanisms by which manipulation exerts such effects remain largely unexplained. The use of fMRI in the animal model has revealed a decrease in cortical activity in response to noxious stimuli following manual joint mobilization. Supraspinal mediation contributing to hypoalgesia in humans may be triggered following spinal manipulation. Ten healthy volunteers (5 women, 5 men) between the ages of 23 and 48 years (mean, 31.2 years) were recruited. Subjects underwent fMRI scanning while receiving noxious stimuli applied to the cuticle of the index finger at a rate of 1 Hz for periods of 15 seconds, alternating with periods of 15 seconds without stimuli, for a total duration of 5 minutes. Subjects then received a supine thrust manipulation directed to the midthoracic spine and were immediately returned to the scanner for reimaging with a second delivery of noxious stimuli. An 11-point numeric pain rating scale was administered immediately after the application of noxious stimuli, premanipulation and postmanipulation. Blood oxygenation level-dependent fMRI recorded the cerebral hemodynamic response to the painful stimuli premanipulation and postmanipulation. The data indicated a significant reduction in subjects' perception of pain (P<.01), as well as a reduction in cerebral blood flow as measured by the blood oxygenation level-dependent response following manipulation to areas associated with the pain matrix (P<.05). There was a significant relationship between reduced activation in the insular cortex and decreased subjective pain ratings on the numeric pain rating scale (r = 0.59, P<.05). This study provides preliminary evidence that suggests that supraspinal mechanisms may be associated with thoracic thrust manipulation and hypoalgesia. However, because the study lacked a control group, the results do not allow for the discernment of the causative effects of manipulation, which may also be related to changes in levels of subjects' fear, anxiety, or expectation of successful outcomes with manipulation. Future investigations should strive to elicit more conclusive findings in the form of randomized clinical trials.

Propofol and memory: a study using a process dissociation procedure and functional magnetic resonance imaging

Thirty volunteers randomly received either mild or deep propofol sedation, to assess its effect on explicit and implicit memory. Blood oxygen level-dependent functional magnetic resonance during sedation examined brain activation by auditory word stimulus and a process dissociation procedure was performed 4 h after scanning. Explicit memory formation did not occur in either group. Implicit memories were formed during mild but not deep sedation (p = 0.04). Mild propofol sedation inhibited superior temporal gyrus activation (Z value 4.37, voxel 167). Deep propofol sedation inhibited superior temporal gyrus (Z value 4.25, voxel 351), middle temporal gyrus (Z value 4.39, voxel 351) and inferior parietal lobule (Z value 5.06, voxel 239) activation. Propofol only abolishes implicit memory during deep sedation. The superior temporal gyrus is associated with explicit memory processing, while the formation of both implicit and explicit memories is associated with superior and middle temporal gyri and inferior parietal lobule activation.

Rhythm-specific modulation of the sensorimotor network in drug-naïve patients with Parkinson’s disease by levodopa

Brain activity during rest is characterized by slow (0.01-0.1 Hz) fluctuations of blood oxygenation level-dependent functional magnetic resonance imaging signals. These fluctuations are organized as functional connectivity networks called resting-state networks, anatomically corresponding to specific neuronal circuits. As Parkinson's disease is mainly characterized by a dysfunction of the sensorimotor pathways, which can be influenced by levodopa administration, the present study investigated the functional connectivity changes within the sensorimotor resting-state network in drug-naïve patients with Parkinson's disease after acute levodopa administration. Using a double-blind placebo-controlled design, resting-state functional magnetic resonance imaging was carried out in 20 drug-naïve patients with Parkinson's disease, immediately before and 60 min after, oral administration of either levodopa or placebo. Control resting-state functional magnetic resonance imaging data were recorded in 18 age- and sex-matched healthy volunteers. Independent component analysis was performed to extract resting-state network maps and associated time-course spectral features. At the anatomical level, levodopa enhanced the sensorimotor network functional connectivity in the supplementary motor area, a region where drug-naïve patients with Parkinson's disease exhibited reduced signal fluctuations compared with untreated patients. At the spectral frequency level, levodopa stimulated these fluctuations in a selective frequency band of the sensorimotor network. The reported effects induced by levodopa on sensorimotor network topological and spectral features confirm that the sensorimotor system is a target of acute levodopa administration in drug-naïve patients with Parkinson's disease. Moreover, while the regional changes in supplementary motor area reflect the functional improvement in motor function, the rhythm-specific modulation induced by the dopamine precursor discloses a novel aspect of pharmacological stimulation in Parkinson's disease, adding further insight to the comprehension of levodopa action.

Interictal cortical hyperresponsiveness in migraine is directly related to the presence of aura

The objective of this study was to compare the interictal cortical response to a visual stimulus between migraine with aura (MWA), migraine without aura (MwoA), and control subjects. In a prospective case-control study, blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) was used to assess the response to a visual stimulus and arterial spin labeled perfusion MR to determine resting cerebral blood flow. A standardized questionnaire was used to assess interictal visual discomfort. Seventy-five subjects (25 MWA, 25 MwoA, and 25 controls) were studied. BOLD fMRI response to visual stimulation within primary visual cortex was greater in MWA (3.09 ± 0.15%) compared to MwoA (2.36 ± 0.13%, P = 0.0008) and control subjects (2.47 ± 0.11%, P = 0.002); responses were also greater in the lateral geniculate nuclei in MWA. No difference was found between MwoA and control groups. Whole brain analysis showed that increased activation in MWA was confined to the occipital pole. Regional resting cerebral blood flow did not differ between groups. MWA and MwoA subjects had significantly greater levels of interictal visual discomfort compared to controls ( P = 0.008 and P = 0.005, respectively), but this did not correlate with BOLD response. Despite similar interictal symptoms of visual discomfort, only MWA subjects have cortical hyperresponsiveness to visual stimulus, suggesting a direct connection between cortical hyperresponsiveness and aura itself.

The hypnotic zolpidem increases the synchrony of BOLD signal fluctuations in widespread brain networks during a resting paradigm

Networks of brain regions having synchronized fluctuations of the blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) time-series at rest, or "resting state networks" (RSNs), are emerging as a basis for understanding intrinsic brain activity. RSNs are topographically consistent with activity-related networks subserving sensory, motor, and cognitive processes, and studying their spontaneous fluctuations following acute drug challenge may provide a way to understand better the neuroanatomical substrates of drug action. The present within-subject double-blind study used BOLD fMRI at 3T to investigate the functional networks influenced by the non-benzodiazepine hypnotic zolpidem (Ambien). Zolpidem is a positive modulator of γ-aminobutyric acid(A) (GABA(A)) receptors, and engenders sedative effects that may be explained in part by how it modulates intrinsic brain activity. Healthy participants (n=12) underwent fMRI scanning 45 min after acute oral administration of zolpidem (0, 5, 10, or 20mg), and changes in BOLD signal were measured while participants gazed at a static fixation point (i.e., at rest). Data were analyzed using group independent component analysis (ICA) with dual regression and results indicated that compared to placebo, the highest dose of zolpidem increased functional connectivity within a number of sensory, motor, and limbic networks. These results are consistent with previous studies showing an increase in functional connectivity at rest following administration of the positive GABA(A) receptor modulators midazolam and alcohol, and suggest that investigating how zolpidem modulates intrinsic brain activity may have implications for understanding the etiology of its powerful sedative effects.

BOLD Responses in Human Primary Visual Cortex are Insensitive to Substantial Changes in Neural Activity

The relationship between blood oxygenation level dependent-functional magnetic resonance imaging (BOLD-fMRI) and magnetoencephalography (MEG) metrics were explored using low-level visual stimuli known to elicit a rich variety of neural responses. Stimuli were either perceptually isoluminant red/green or luminance-modulated black/yellow square-wave gratings with spatial frequencies of 0.5, 3, and 6 cycles per degree. Neural responses were measured with BOLD-fMRI (3-tesla) and whole head MEG. For all stimuli, the BOLD response showed bilateral activation of early visual cortex that was greater in the contralateral hemisphere. There was variation between individuals but weak, or no evidence, of amplitude dependence on either spatial frequency or the presence of luminance contrast. In contrast, beamformer analysis of MEG data showed activation in contralateral early visual cortex and revealed: (i) evoked responses with stimulus-dependent amplitude and latency; (ii) gamma and high-beta oscillations, with spatial frequency dependent peaks at approximately 30 and 50 Hz, but only for luminance-modulated gratings; (iii) The gamma and beta oscillations appeared to show different spatial frequency tuning profiles; (iv) much weaker gamma and beta responses, and at higher oscillation frequencies, for isoluminant compared to luminance-modulated gratings. The results provide further evidence that the relationship between the fMRI-BOLD response and cortical neural activity is complex, with BOLD-fMRI being insensitive to substantial changes in neural activity. All stimuli were clearly visible to participants and so the paucity of gamma oscillations to isoluminant stimuli is inconsistent with theories of their role in conscious visual perception.

Astrocytes: can they be the missing stars linking neuronal activity to neurofunctional imaging signals?

Functional neuroimaging techniques are currently used in fundamental neuroscience as well as in cognitive neuroscience and clinics to study brain function at large spatial scales. They include Blood Oxygenation Level Dependent-functional Magnetic Resonance Imaging (BOLD-fMRI, Kim and Ogawa, 2012), the gold standard of functional neuroimaging techniques, and many optical techniques including functional Near InfraRed Spectroscopy (fNIRS) in human research or intrinsic/spectroscopic optical signal (IOS) imaging in animal research (Devor et al., 2012). These techniques rely on vascular signals [cerebral blood flow (CBF) and volume and metabolic rate of oxygen consumption] that constitute a proxy for neuronal activity because of the existence of functional hyperemia, a mechanism defined as the matching of vascular changes to the activity level in a given brain area (Iadecola and Nedergaard, 2007). To date, some crucial open questions remain concerning these functional signals, including: what kind of brain activity are they related to? What are their cellular/molecular sources? Can astrocytes, in addition to roles in translating neuronal into vascular activity, also be capable of generating functional neuroimaging signals on their own?

Sex-based fMRI differences in obese humans in response to high vs. low energy food cues

Gender specific effects on human eating have been previously reported. Here we investigated sex-based differences in neural activation via whole-brain blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in response to high energy-dense (high-ED) vs. low-ED visual and auditory food cues in obese men vs. women in both fed and fasted states. The results show that in response to high vs. low ED foods in the fed state, obese men (vs. women) had greater activation in brain areas associated with motor control regions (e.g. supplementary motor areas) whereas women showed greater activation in cognitive-related regions. In the fasted state, obese men had greater activation in a visual-attention region whereas obese women showed greater activation in affective and reward related processing regions (e.g. caudate). Overall the results support our a priori hypothesis that obese women (vs. men) have greater neural activation in regions associated with cognition and emotion-related brain regions. These findings may improve our understanding of sex specific differences among obese individuals in eating behavior.

Fronto‐striatal functional connectivity during response inhibition in alcohol dependence

Poor response inhibition has been implicated in the development of alcohol dependence, yet little is known about how neural pathways underlying cognitive control are affected in this disorder. Moreover, endogenous opioid levels may impact the functionality of inhibitory control pathways. This study investigated the relationship between alcohol dependence severity and functional connectivity of fronto-striatal networks during response inhibition in an alcohol-dependent sample. A secondary aim of this study was to test the moderating effect of a functional polymorphism (A118G) of the μ-opioid receptor (OPRM1) gene. Twenty individuals with alcohol dependence (six females; 90% Caucasian; mean age = 29.4) who were prospectively genotyped on the OPRM1 gene underwent blood oxygen level-dependent functional magnetic resonance imaging while performing a Stop-Signal Task. The relationship between alcohol dependence severity and functional connectivity within fronto-striatal networks important for response inhibition was assessed using psychophysiological interaction analyses. Analyses revealed greater alcohol dependence severity was associated with weaker functional connectivity between the putamen and prefrontal regions (e.g. the anterior insula, anterior cingulate and medial prefrontal cortex) during response inhibition. Furthermore, the OPRM1 genotype was associated with differential response inhibition-related functional connectivity. This study demonstrates that individuals with more severe alcohol dependence exhibit less frontal connectivity with the striatum, a component of cognitive control networks important for response inhibition. These findings suggest that the fronto-striatal pathway underlying response inhibition is weakened as alcoholism progresses.

Complexity and synchronicity of resting state blood oxygenation level-dependent (BOLD) functional MRI in normal aging and cognitive decline

To explore the use of approximate entropy (ApEn) as an index of the complexity and the synchronicity of resting state blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in normal aging and cognitive decline associated with familial Alzheimer's disease (fAD).Resting state BOLD fMRI data were acquired at 3T from two independent cohorts of subjects consisting of healthy young (age 23 ± 2 years, n = 8) and aged volunteers (age 66 ± 3 years, n = 8), as well as 22 fAD associated subjects (14 mutation carriers, age 41.2 ± 15.8 years; and eight nonmutation carrying family members, age 28.8 ± 5.9 years). Mean ApEn values were compared between the two age groups and correlated with cognitive performance in the fAD group. Cross-ApEn (C-ApEn) was further calculated to assess the asynchrony between precuneus and the rest of the brain.Complexity of brain activity measured by mean ApEn in gray and white matter decreased with normal aging. In the fAD group, cognitive impairment was associated with decreased mean ApEn in gray matter as well as decreased regional ApEn in right precuneus, right lateral parietal regions, left precentral gyrus, and right paracentral gyrus. A pattern of asynchrony between BOLD fMRI series emerged from C-ApEn analysis, with significant regional anti-correlation with cross-correlation coefficient of functional connectivity analysis.ApEn and C-ApEn may be useful for assessing the complexity and synchronicity of brain activity in normal aging and cognitive decline associated with neurodegenerative diseases.

Information Processing Architecture of Functionally Defined Clusters in the Macaque Cortex

Computational and empirical neuroimaging studies have suggested that the anatomical connections between brain regions primarily constrain their functional interactions. Given that the large-scale organization of functional networks is determined by the temporal relationships between brain regions, the structural limitations may extend to the global characteristics of functional networks. Here, we explored the extent to which the functional network community structure is determined by the underlying anatomical architecture. We directly compared macaque (Macaca fascicularis) functional connectivity (FC) assessed using spontaneous blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) to directed anatomical connectivity derived from macaque axonal tract tracing studies. Consistent with previous reports, FC increased with increasing strength of anatomical connection, and FC was also present between regions that had no direct anatomical connection. We observed moderate similarity between the FC of each region and its anatomical connectivity. Notably, anatomical connectivity patterns, as described by structural motifs, were different within and across functional modules: partitioning of the functional network was supported by dense bidirectional anatomical connections within clusters and unidirectional connections between clusters. Together, our data directly demonstrate that the FC patterns observed in resting-state BOLD-fMRI are dictated by the underlying neuroanatomical architecture. Importantly, we show how this architecture contributes to the global organizational principles of both functional specialization and integration.

Evidence that hippocampal–parahippocampal dysfunction is related to genetic risk for schizophrenia

Abnormalities in hippocampal-parahippocampal (H-PH) function are prominent features of schizophrenia and have been associated with deficits in episodic memory. However, it remains unclear whether these abnormalities represent a phenotype related to genetic risk for schizophrenia or whether they are related to disease state. We investigated H-PH-mediated behavior and physiology, using blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI), during episodic memory in a sample of patients with schizophrenia, clinically unaffected siblings and healthy subjects. Patients with schizophrenia and unaffected siblings displayed abnormalities in episodic memory performance. During an fMRI memory encoding task, both patients and siblings demonstrated a similar pattern of reduced H-PH engagement compared with healthy subjects. Our findings suggest that the pathophysiological mechanism underlying the inability of patients with schizophrenia to properly engage the H-PH during episodic memory is related to genetic risk for the disorder. Therefore, H-PH dysfunction can be assumed as a schizophrenia susceptibility-related phenotype.

Low-frequency oscillations measured in the periphery with near-infrared spectroscopy are strongly correlated with blood oxygen level-dependent functional magnetic resonance imaging signals

Low-frequency oscillations (LFOs) in the range of 0.01-0.15 Hz are commonly observed in functional imaging studies, such as blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) and functional near-infrared spectroscopy (fNIRS). Some of these LFOs are nonneuronal and are closely related to autonomic physiological processes. In the current study, we conducted a concurrent resting-state fMRI and NIRS experiment with healthy volunteers. LFO data was collected simultaneously at peripheral sites (middle fingertip and big toes) by NIRS, and centrally in the brain by BOLD fMRI. The cross-correlations of the LFOs collected from the finger, toes, and brain were calculated. Our data show that the LFOs measured in the periphery (NIRS signals) and in the brain (BOLD fMRI) were strongly correlated with varying time delays. This demonstrates that some portion of the LFOs actually reflect systemic physiological circulatory effects. Furthermore, we demonstrated that NIRS is effective for measuring the peripheral LFOs, and that these LFOs and the temporal shifts between them are consistent in healthy participants and may serve as useful biomarkers for detecting and monitoring circulatory dysfunction.

FKBP5 and emotional neglect interact to predict individual differences in amygdala reactivity

Individual variation in physiological responsiveness to stress mediates risk for mental illness and is influenced by both experiential and genetic factors. Common polymorphisms in the human gene for FK506 binding protein 5 (FKBP5), which is involved in transcriptional regulation of the hypothalamic-pituitary-adrenal (HPA) axis, have been shown to interact with childhood abuse and trauma to predict stress-related psychopathology. In the current study, we examined if such gene-environment interaction effects may be related to variability in the threat-related reactivity of the amygdala, which plays a critical role in mediating physiological and behavioral adaptations to stress including modulation of the HPA axis. To this end, 139 healthy Caucasian youth completed a blood oxygen level-dependent functional magnetic resonance imaging probe of amygdala reactivity and self-report assessments of emotional neglect (EN) and other forms of maltreatment. These individuals were genotyped for 6 FKBP5 polymorphisms (rs7748266, rs1360780, rs9296158, rs3800373, rs9470080 and rs9394309) previously associated with psychopathology and/or HPA axis function. Interactions between each SNP and EN emerged such that risk alleles predicted relatively increased dorsal amygdala reactivity in the context of higher EN, even after correcting for multiple testing. Two different haplotype analyses confirmed this relationship as haplotypes with risk alleles also exhibited increased amygdala reactivity in the context of higher EN. Our results suggest that increased threat-related amygdala reactivity may represent a mechanism linking psychopathology to interactions between common genetic variants affecting HPA axis function and childhood trauma.

Visualization of Altered Neurovascular Coupling in Chronic Stroke Patients using Multimodal Functional MRI

Evaluation of cortical reorganization in chronic stroke patients requires methods to accurately localize regions of neuronal activity. Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is frequently employed; however, BOLD contrast depends on specific coupling relationships between the cerebral metabolic rate of oxygen (CMRO(2)), cerebral blood flow (CBF), and volume (CBV), which may not exist following stroke. The aim of this study was to understand whether CBF-weighted (CBFw) and CBV-weighted (CBVw) fMRI could be used in sequence with BOLD to characterize neurovascular coupling mechanisms poststroke. Chronic stroke patients (n=11) with motor impairment and age-matched controls (n=11) performed four sets of unilateral motor tasks (60 seconds/30 seconds off/on) during CBFw, CBVw, and BOLD fMRI acquisition. While control participants elicited mean BOLD, CBFw, and CBVw responses in motor cortex (P<0.01), patients showed only mean changes in CBF (P<0.01) and CBV (P<0.01), but absent mean BOLD responses (P=0.20). BOLD intersubject variability was consistent with differing coupling indices between CBF, CBV, and CMRO(2). Thus, CBFw and/or CBVw fMRI may provide crucial information not apparent from BOLD in these patients. A table is provided outlining distinct vascular and metabolic uncoupling possibilities that elicit different BOLD responses, and the strengths and limitations of the multimodal protocol are summarized.

Origins of intersubject variability of blood oxygenation level dependent and arterial spin labeling fMRI: implications for quantification of brain activity

Accurate localization of brain activity using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been challenged because of the large BOLD signal within distal veins. Arterial spin labeling (ASL) techniques offer greater sensitivity to the microvasculature but possess low temporal resolution and limited brain coverage. In this study, we show that the physiological origins of BOLD and ASL depend on whether percent change or statistical significance is being considered. For BOLD and ASL fMRI data collected during a simple unilateral hand movement task, we found that in the area of the contralateral motor cortex the centre of gravity (CoG) of the intersubject coefficient of variation (CV) of BOLD fMRI was near the brain surface for percent change in signal, whereas the CoG of the intersubject CV for Z-score was in close proximity of sites of brain activity for both BOLD and ASL. These findings suggest that intersubject variability of BOLD percent change is vascular in origin, whereas the origin of inter-subject variability of Z-score is neuronal for both BOLD and ASL. For longer duration tasks (12 s or greater), however, there was a significant correlation between BOLD and ASL percent change, which was not evident for short duration tasks (6 s). These findings suggest that analyses directly comparing percent change in BOLD signal between pre-defined regions of interest using short duration stimuli, as for example in event-related designs, may be heavily weighted by large-vessel responses rather than neuronal responses.