Resting-state Cerebral Blood Flow Research Articles

Test-retest reliability of resting-state cerebral blood flow quantification using pulsed Arterial Spin Labeling (PASL) over 3 weeks vs 8 weeks in healthy controls

Arterial Spin Labeling is a valuable functional imaging tool for both clinical and research purposes. However, little is known about the test-retest reliability of cerebral blood flow measurements over longer periods. In this study, we investigated the reliability of pulsed Arterial Spin Labeling in assessing cerebral blood flow over a 3 (n = 28) vs 8 (n = 19) weeks interscan interval in 47 healthy participants. As a measure of cerebral blood flow reliability, we calculated voxel-wise, whole-brain, and regions of interest intraclass correlation coefficients. The whole-brain mean resting-state cerebral blood flow showed good to excellent reliability over time for both periods (intraclass correlation coefficients = 0.85 for the 3-week delay, intraclass correlation coefficients = 0.53 for the 8-week delay). However, the voxel-wise and regions of interest intraclass correlation coefficients fluctuated at 8-week compared to the 3-week interval, especially within cortical areas. These results confirmed previous findings that Arterial Spin Labeling could be used as a reliable method to assess brain perfusion. However, as the reliability seemed to decrease over time, caution is warranted when performing correlations with other variables, especially in clinical populations.

Resting-state cerebral blood flow and functional connectivity abnormalities in depressed patients with childhood maltreatment: Potential biomarkers of vulnerability?

Childhood maltreatment (CM) is an important risk factor for major depressive disorder (MDD). This study aimed to explore the specific effect of CM on cerebral blood flow (CBF) and brain functional connectivity (FC) in MDD patients. A total of 150 subjects were collected including 55 MDD patients with CM, 34 MDD patients without CM, 19 healthy controls (HC) with CM, and 42 HC without CM. All subjects completed MRI scans and neuropsychological tests. Two-way analysis of covariance was used to detect the main and interactive effects of disease and CM on CBF and FC across subjects. Then, partial correlation analyses were conducted to explore the behavioral significance of altered CBF and FC in MDD patients. Finally, a support vector classifier model was applied to differentiate MDD patients. MDD patients represented increased CBF in bilateral temporal lobe and decreased CBF in right visual cortex. Importantly, significant depression-by-CM interactive effects on CBF were primarily located in the frontoparietal regions, including orbitofrontal cortex (OFC), lateral prefrontal cortex (PFC), and parietal cortex. Moreover, significant FC abnormalities were seen in OFC-PFC and frontoparietal-visual cortex. Notably, the abnormal CBF and FC were significantly associated with behavioral performance. Finally, a combination of altered CBF and FC behaved with a satisfactory classification ability to differentiate MDD patients. These results highlight the importance of frontoparietal and visual cortices for MDD with CM experience, proposing a potential neuroimaging biomarker for MDD identification.

Resting-state perfusion in motor and fronto-limbic areas is linked to diminished expression of emotion and speech in schizophrenia

Negative symptoms (NS) are a core component of schizophrenia affecting community functioning and quality of life. We tested neural correlates of NS considering NS factors and consensus subdomains. We assessed NS using the Clinical Assessment Interview for Negative Symptoms and the Scale for Assessment of Negative Symptoms. Arterial spin labeling was applied to measure resting-state cerebral blood flow (rCBF) in 47 schizophrenia patients and 44 healthy controls. Multiple regression analyses calculated the relationship between rCBF and NS severity. We found an association between diminished expression (DE) and brain perfusion within the cerebellar anterior lobe and vermis, and the pre-, and supplementary motor area. Blunted affect was linked to fusiform gyrus and alogia to fronto-striatal rCBF. In contrast, motivation and pleasure was not associated with rCBF. These results highlight the key role of motor areas for DE. Considering NS factors and consensus subdomains may help identifying specific pathophysiological pathways of NS.

Three potential neurovascular pathways driving the benefits of mindfulness meditation for older adults.

Mindfulness meditation has been shown to be beneficial for a range of different health conditions, impacts brain function and structure relatively quickly, and has shown promise with aging samples. Functional magnetic resonance imaging metrics provide insight into neurovascular health which plays a key role in both normal and pathological aging processes. Experimental mindfulness meditation studies that included functional magnetic resonance metrics as an outcome measure may point to potential neurovascular mechanisms of action relevant for aging adults that have not yet been previously examined. We first review the resting-state magnetic resonance studies conducted in exclusively older adult age samples. Findings from older adult-only samples are then used to frame the findings of task magnetic resonance imaging studies conducted in both clinical and healthy adult samples. Based on the resting-state studies in older adults and the task magnetic resonance studies in adult samples, we propose three potential mechanisms by which mindfulness meditation may offer a neurovascular therapeutic benefit for older adults: (1) a direct neurovascular mechanism via increased resting-state cerebral blood flow; (2) an indirect anti-neuroinflammatory mechanism via increased functional connectivity within the default mode network, and (3) a top-down control mechanism that likely reflects both a direct and an indirect neurovascular pathway.

Cerebral blood flow changes in schizophrenia patients with auditory verbal hallucinations during low-frequency rTMS treatment.

Auditory verbal hallucinations (AVH) are a prominent symptom of schizophrenia. Low-frequency repetitive transcranial magnetic stimulation (rTMS) has been evidenced to improve the treatment of AVH in schizophrenia. Although abnormalities in resting-state cerebral blood flow (CBF) have been reported in schizophrenia, the perfusion alterations specific to schizophrenia patients with AVH during rTMS require further investigation. In this study, we used arterial spin labeling (ASL) to investigate changes in brain perfusion in schizophrenia patients with AVH, and their associations with clinical improvement following low-frequency rTMS treatment applied to the left temporoparietal junction area. We observed improvements in clinical symptoms (e.g., positive symptoms and AVH) and certain neurocognitive functions (e.g., verbal learning and visual learning) following treatment. Furthermore, at baseline, the patients showed reductions in CBF in regions associated with language, sensory, and cognition compared to controls, primarily located in the prefrontal cortices (e.g., left inferior frontal gyrus and left middle frontal gyrus), occipital lobe (e.g., left calcarine cortex), and cingulate cortex (e.g., bilateral middle cingulate cortex), compared to controls. Conversely, we observed increased CBF in the left inferior temporal gyrus and bilateral putamen in patients relative to controls, regions known to be involved in AVH. However, the hypoperfusion or hyperperfusion patterns did not persist and instead were normalized, and were related to clinical response (e.g., AVH) in patients during low-frequency rTMS treatment. Importantly, the changes in brainperfusion were related to clinical response (e.g., AVH) in patients. Our findings suggest that low-frequency rTMS can regulate brain perfusion involving critical circuits by its remote effect in schizophrenia, and may play an important mechanistic role in the treatment of AVH.

Altered neurovascular coupling in the children with attention-deficit/hyperactivity disorder: a comprehensive fMRI analysis.

The coupling between resting-state cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) signals reflects the mechanism of neurovascular coupling (NVC), which have not been illustrated in attention-deficit/hyperactivity disorder (ADHD). Fifty ADHD and 42 age- and gender-matched typically developing controls (TDs) were enrolled. The NVC imaging metrics were investigated by exploring the Pearson correlation coefficients between CBF and BOLD-derived quantitative maps (ALFF, fALFF, DCP maps). Three types of NVC metrics (CBF-ALFF, CBF-fALFF, CBF-DCP coupling) were compared between ADHD and TDs group, and the inner association between altered NVC metrics and clinical variables in ADHD group was further analyzed. Compared to TDs, ADHD showed significantly reduced whole-brain CBF-ALFF coupling (P < 0.001). Among regional level (all PFDR < 0.05), ADHD showed significantly lower CBF-ALFF coupling in bilateral thalamus, default-mode network (DMN) involving left anterior cingulate (ACG.L) and right parahippocampal gyrus (PHG.R), execution control network (ECN) involving right middle orbital frontal gyrus (ORBmid.R) and right inferior frontal triangular gyrus (IFGtriang.R), and increased CBF-ALFF coupling in attention network (AN)-related left superior temporal gyrus (STG.L) and somatosensory network (SSN))-related left rolandic operculum (ROL.L). Furthermore, increased CBF-fALFF coupling was found in the visual network (VN)-related left cuneus and negatively correlated with the concentration index of ADHD (R = - 0.299, PFDR = 0.035). Abnormal regional NVC metrics were at widespread neural networks in ADHD, mainly involved in DMN, ECN, SSN, AN, VN and bilateral thalamus. Notably, this study reinforced the insights into the neural basis and pathophysiological mechanism underlying ADHD.

Altered coupling of resting-state cerebral blood flow and functional connectivity in Meige syndrome.

Meige syndrome (MS) is an adult-onset segmental dystonia disease, mainly manifested as blepharospasm and involuntary movement caused by dystonic dysfunction of the oromandibular muscles. The changes of brain activity, perfusion and neurovascular coupling in patients with Meige syndrome are hitherto unknown. Twenty-five MS patients and thirty age- and sex-matched healthy controls (HC) were prospectively recruited in this study. All the participants underwent resting-state arterial spin labeling and blood oxygen level-dependent examinations on a 3.0 T MR scanner. The measurement of neurovascular coupling was calculated using cerebral blood flow (CBF)-functional connectivity strength (FCS) correlations across the voxels of whole gray matter. Also, voxel-wised analyses of CBF, FCS, and CBF/FCS ratio images between MS and HC were conducted. Additionally, CBF and FCS values were compared between these two groups in selected motion-related brain regions. MS patients showed increased whole gray matter CBF-FCS coupling relative to HC (t = 2.262, p = 0.028). In addition, MS patients showed significantly increased CBF value in middle frontal gyrus and bilateral precentral gyrus. The abnormal elevated neurovascular coupling of MS may indicate a compensated blood perfusion in motor-related brain regions and reorganized the balance between neuronal activity and brain blood supply. Our results provide a new insight into the neural mechanism underlying MS from the perspective of neurovascular coupling and cerebral perfusion.

Neural Correlates of Formal Thought Disorder Dimensions in Psychosis.

Formal thought disorder (FTD) is a core symptom of psychosis, but its neural correlates remain poorly understood. This study tested whether four FTD dimensions differ in their association with brain perfusion and brain structure. This cross-sectional study investigated 110 patients with schizophrenia spectrum disorders using 3T magnetic resonance imaging (MRI). The Thought and Language Disorder scale (TALD) was utilized, which comprises four subscales: Objective Positive (OP), Objective Negative (ON), Subjective Positive (SP), and Subjective Negative (SN). Resting-state cerebral blood flow (rsCBF), cortical thickness (CortTh), gray matter volume (GMV), and diffusion MRI tractography were tested for associations with TALD subscales controlling for age, medication, total intracranial volume, and for variance of the 3 other TALD subscales. Following Bonferroni correction, the FTD dimensions presented distinct neural correlates. OP scores were associated with increased rsCBF and increased GMV in the right cerebellum lingual gyrus. Higher SP scores were linked to increased GMV in bilateral prefrontal cortex. In contrast, ON was associated with increased GMV in the right premotor cortex. At more liberal statistical thresholds, higher SP was associated with increased CortTh in the right inferior frontal gyrus, whereas SN scores were linked to decreased GMV in the right prefrontal lobe, the left inferior temporal gyrus, and the left supplementary motor area. Unadjusted analyses mostly corroborated these findings. These findings stress the heterogeneity in FTD, suggesting distinct neural patterns for specific FTD experiences. In sum, FTD in psychosis may require distinct treatment strategies and further mechanistic investigations on single-item levels.

Lithium bidirectionally regulates depression- and mania-related brain functional alterations without worsening cognitive function in patients with bipolar disorder.

Lithium monotherapy has been proposed to have antidepressant and antimanic effects in patients with bipolar disorder (BP). However, so far, it is lack of evidence to support this proposition. The main aim of this study was to test the hypothesis that lithium bidirectionally regulates depression- and mania-related brain functional abnormalities in patients with BP. We also assessed the effects of lithium, alone and in combination with other pharmacological treatments, on patients' cognitive performance. We enrolled 149 drug-naïve patients with BP; 99 patients experiencing first depressive episodes were allocated randomly to four treatment groups [lithium (DP/Li), lithium with lamotrigine (LTG; DP/Li+LTG), LTG (DP/LTG), and valproate (VPA) with LTG (DP/VPA+LTG)], and 50 experiencing first hypo-manic episodes were allocated to two treatment groups (MA/Li and MA/VPA). For comparative analysis, 60 age-matched healthy individuals were also recruited. Whole-brain global and regional resting-state cerebral blood flow (rs-CBF) and cognitive alterations were examined before and after 12-week treatment. We have the following findings: DP/Li+LTG, and to a lesser extent DP/Li, alleviated the depression-related reduction in rs-CBF. MA/VPA and MA/Li reversed the mania-related elevation of rs-CBF completely and partially, respectively. Lithium alone improved cognitive performance during depressive and manic episodes; other tested treatments have no such effect or worsened cognitive ability. Our results showed that lithium bidirectionally regulates depression- and mania-associated brain functional abnormalities in patients with BP. Lithium monotherapy has a better antimanic effect than VPA, is superior to other tested treatments in improving cognition during the course of BP, and has satisfactory antidepressant effects in patients with BP.

Altered Coupling of Cerebral Blood Flow and Functional Connectivity Strength in First-Episode Schizophrenia Patients With Auditory Verbal Hallucinations.

ObjectiveAuditory verbal hallucinations (AVHs) are a major symptom of schizophrenia and are connected with impairments in auditory and speech-related networks. In schizophrenia with AVHs, alterations in resting-state cerebral blood flow (CBF) and functional connectivity have been described. However, the neurovascular coupling alterations specific to first-episode drug-naïve schizophrenia (FES) patients with AVHs remain unknown.MethodsResting-state functional MRI and arterial spin labeling (ASL) was performed on 46 first-episode drug-naïve schizophrenia (FES) patients with AVHs (AVH), 39 FES drug-naïve schizophrenia patients without AVHs (NAVH), and 48 healthy controls (HC). Then we compared the correlation between the CBF and functional connection strength (FCS) of the entire gray matter between the three groups, as well as the CBF/FCS ratio of each voxel. Correlation analyses were performed on significant results between schizophrenia patients and clinical measures scale.ResultsThe CBF/FCS ratio was reduced in the cognitive and emotional brain regions in both the AVH and NAVH groups, primarily in the crus I/II, vermis VI/VII, and cerebellum VI. In the AVH group compared with the HC group, the CBF/FCS ratio was higher in auditory perception and language-processing areas, primarily the left superior and middle temporal gyrus (STG/MTG). The CBF/FCS ratio in the left STG and left MTG positively correlates with the score of the Auditory Hallucination Rating Scale in AVH patients.ConclusionThese findings point to the difference in neurovascular coupling failure between AVH and NAVH patients. The dysfunction of the forward model based on the predictive and computing role of the cerebellum may increase the excitability in the auditory cortex, which may help to understand the neuropathological mechanism of AVHs.

Altered resting-state cerebral blood flow and functional connectivity mediate suicidal ideation in major depressive disorder

The relationships among cerebral blood flow (CBF), functional connectivity (FC) and suicidal ideation (SI) in major depressive disorder (MDD) patients have remained elusive. In this study, we characterized the changes in CBF and FC among 175 individuals including 47 MDD without SI (MDDNSI), 59 MDD with SI (MDDSI), and 69 healthy control (HC) who underwent arterial spin labeling and resting-state functional MRI scans. Then the voxel-wise CBF, seed-based FC and partial correlation analyses were measured. Mediation analysis was carried out to reveal the effects of FC on the association between CBF and behavioral performances in both subgroups. Results showed that CBF was higher in MDDSI patients in the bilateral precuneus compared to HC and MDDNSI participants. MDDSI patients exhibited enhanced FC in the prefrontal-limbic system and decreased FC in the sensorimotor cortex (SMC) relative to MDDNSI patients. CBF and FC were significantly correlated with clinical variables. More importantly, exploratory mediation analyses identified that abnormal FC can mediate the association between regional CBF and behavioral performances. These results highlight the potential role of precuneus gyrus, prefrontal-limbic system as well as SMC in the process of suicide and provide new insights into the neural mechanism underlying suicide in MDD patients.

Aberrant pattern of cerebral blood flow in patients with major depressive disorder: A meta-analysis of arterial spin labelling studies

BackgroundAccumulating evidence has suggested that patients with major depressive disorder (MDD) could exhibit resting-state cerebral blood flow (CBF) abnormalities. However, findings across studies are controversial. MethodsOur study aimed at identifying replicable CBF changes in MDD by conducting a case-control meta-analysis and meta-regression of arterial spin labelling studies using seed-based d mapping software. Fourteen studies encompassing 505 patients with MDD and 443 healthy controls were included. ResultsWe found increased CBF in the inferior parietal lobule, the striatum, and the bilateral thalamus in all patients with MDD relative to healthy controls. While decreased CBF was observed in the inferior frontal gyrus, the insula, the middle occipital gyrus and the bilateral superior temporal gyrus in patients with MDD. Moreover, increased CBF of the bilateral thalamus was associated with more severe depressive symptoms in patients with MDD. The subgroup meta-analysis showed that patients with acute phase had increased CBF in the bilateral thalamus, and decreased CBF in the left middle occipital gyrus and the left middle frontal gyrus. Chronic patients had decreased CBF in the left insula, the right calcarine sulcus, the right inferior frontal gyrus, and the left parahippocampal gyrus. Patients with medication-free had increased CBF in the right anterior cingulate cortex/medial prefrontal cortex, and decreased CBF in the left middle occipital gyrus, the left inferior frontal gyrus, and the left precentral gyrus. ConclusionsThese findings suggest an aberrant cerebral blood flow pattern of MDD involving the cortico-striatal-thalamic circuit, which may facilitate understanding of pathophysiology and suggest potential neural biomarkers for clinical assessment, monitoring and interventions of MDD. One important limitation is that eight recruited studies in our meta-analysis have recruited more males than females, which may have a selection bias of patients.

Laminar perfusion imaging with zoomed arterial spin labeling at 7 Tesla

Laminar fMRI based on BOLD and CBV contrast at ultrahigh magnetic fields has been applied for studying the dynamics of mesoscopic brain networks. However, the quantitative interpretations of BOLD/CBV fMRI results are confounded by different baseline physiology across cortical layers. Here we introduce a novel 3D zoomed pseudo-continuous arterial spin labeling (pCASL) technique at 7T that offers the capability for quantitative measurements of laminar cerebral blood flow (CBF) both at rest and during task activation with high spatial specificity and sensitivity. We found arterial transit time in superficial layers is ∼100 ms shorter than in middle/deep layers revealing the time course of labeled blood flowing from pial arteries to downstream microvasculature. Resting state CBF peaked in the middle layers which is highly consistent with microvascular density measured from human cortex specimens. Finger tapping induced a robust two-peak laminar profile of CBF increases in the superficial (somatosensory and premotor input) and deep (spinal output) layers of M1, while finger brushing task induced a weaker CBF increase in superficial layers (somatosensory input). This observation is highly consistent with reported laminar profiles of CBV activation on M1. We further demonstrated that visuospatial attention induced a predominant CBF increase in deep layers and a smaller CBF increase on top of the lower baseline CBF in superficial layers of V1 (feedback cortical input), while stimulus driven activity peaked in the middle layers (feedforward thalamic input). With the capability for quantitative CBF measurements both at baseline and during task activation, high-resolution ASL perfusion fMRI at 7T provides an important tool for in vivo assessment of neurovascular function and metabolic activities of neural circuits across cortical layers.

Altered Coupling Between Resting-State Cerebral Blood Flow and Functional Connectivity Strength in Cervical Spondylotic Myelopathy Patients.

Background: Changes in regional neural activity and functional connectivity in cervical spondylotic myelopathy (CSM) patients have been reported. However, resting-state cerebral blood flow (CBF) changes and coupling between CBF and functional connectivity in CSM patients are largely unknown.Methods: Twenty-seven CSM patients and 24 sex/age-matched healthy participants underwent resting-state functional MRI and arterial spin labeling imaging to compare functional connectivity strength (FCS) and CBF between the two groups. The CBF–FCS coupling of the whole gray matter and specific regions of interest was also compared between the groups.Results: Compared with healthy individuals, CBF–FCS coupling was significantly lower in CSM patients. The decrease in CBF–FCS coupling in CSM patients was observed in the superior frontal gyrus, bilateral thalamus, and right calcarine cortex, whereas the increase in CBF–FCS coupling was observed in the middle frontal gyrus. Moreover, low CBF and high FCS were observed in sensorimotor cortices and visual cortices, respectively.Conclusion: In general, neurovascular decoupling at cortical level may be a potential neuropathological mechanism of CSM.

A pilot study exploring the effect of repetitive transcranial magnetic stimulation (rTMS) treatment on cerebral blood flow and its relation to clinical outcomes in severe enduring anorexia nervosa

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is a novel treatment option for people with severe enduring anorexia nervosa (SE-AN), but associated neurobiological changes are poorly understood. This study investigated the effect of rTMS treatment on regional cerebral blood flow (CBF) and whether any observed changes in CBF are associated with changes in clinical outcomes in people with SE-AN.MethodsAs part of a randomised sham-controlled feasibility trial of 20 sessions of high-frequency rTMS to the left dorsolateral prefrontal cortex, 26 of 34 trial participants completed arterial spin labelling (ASL) functional magnetic resonance imaging (fMRI) to quantify regional and global resting state CBF before (pre-randomisation baseline) and after real or sham treatment (1-month post-randomisation). A group of healthy females (n = 30) were recruited for baseline comparison. Clinical outcomes, including BMI, and depression and anxiety symptoms, were assessed at baseline, 1-, 4-, and 18-months post-randomisation.ResultsNo group differences in regional CBF were identified between the SE-AN and healthy comparison participants. A significant treatment-by-time interaction in a medial temporal lobe cluster with the maximal peak in the right amygdala was identified, reflecting a greater reduction in amygdala CBF following real rTMS compared to sham. Participants with the greatest rTMS-related reduction in amygdala CBF (i.e., between baseline and 1-month post-randomisation) showed the greatest sustained weight gain at 18-months post-randomisation. Higher baseline CBF in the insula predicted greater weight gain between baseline and 1-month post-randomisation and between baseline and 4-months post-randomisation.ConclusionsThis exploratory pilot study identified rTMS treatment related changes in CBF in adults with SE-AN and these were associated with changes in weight. Our preliminary findings also suggest that CBF (as measured by ASL fMRI) may be a marker of rTMS treatment response in this patient group. Future rTMS studies in AN should employ longitudinal neuroimaging to further explore the neurobiological changes related to rTMS treatment.Trial registrationISRCTN14329415, registered 23rd July 2015.

Altered Neurovascular Coupling in Patients with Chronic Myofascial Pain

Despite previous reports on cerebral structures and functional connectivity in patients with myofascial pain (MFP), it is not clear whether alterations in neurovascular coupling occur in these patients. We analyzed the coupling between resting-state cerebral blood flow (CBF) and functional connectivity strength (FCS) for observation of neurovascular coupling in patients with chronic MFP. Observational study. University hospital. Resting-state functional magnetic resonance imaging and arterial spin labeling were performed in 23 patients with chronic MFP and 23 healthy controls (HC) for the calculation of FCS and CBF. The whole-brain gray matter CBF-FCS correlations and CBF/FCS ratios of the various voxels of the 2 groups were subsequently compared. Compared with the HC, the patients with MFP experienced a decrease in whole-brain gray matter CBF-FCS coupling. In patients with MFP, a decrease in CBF/FCS was found in the bilateral superior temporal gyri, right parahippocampal gyrus, right hippocampus, caudate nucleus, right medial prefrontal cortex, and the periaqueductal gray matter (PAG), whereas an increase in CBF/FCS was found in the bilateral lingual gyri, posterior cingulate cortex, and bilateral inferior parietal lobules. In addition, the CBF/FCS of the PAG in patients with MFP was significantly negatively correlated with the pain visual analog scale score and pain duration. Alterations in neurovascular coupling in patients with MFP were observed only before treatment. Therefore, there is a lack of data on the alterations that occurred after treatment. This study demonstrated for the first time that impairment of neurovascular coupling in the brain may be a potential neuropathological mechanism of chronic MFP.

Evaluation of Arterial Spin Labeling MRI-Comparison with 15O-Water PET on an Integrated PET/MR Scanner.

Cerebral blood flow (CBF) measurements are of high clinical value and can be acquired non-invasively with no radiation exposure using pseudo-continuous arterial spin labeling (ASL). The aim of this study was to evaluate accordance in resting state CBF between ASL (CBFASL) and 15O-water positron emission tomography (PET) (CBFPET) acquired simultaneously on an integrated 3T PET/MR system. The data comprised ASL and dynamic 15O-water PET data with arterial blood sampling of eighteen subjects (eight patients with focal epilepsy and ten healthy controls, age 21 to 61 years). 15O-water PET parametric CBF images were generated using a basis function implementation of the single tissue compartment model. Cortical and subcortical regions were automatically segmented using Freesurfer. Average CBFASL and CBFPET in grey matter were 60 ± 20 and 75 ± 22 mL/100 g/min respectively, with a relatively high correlation (r = 0.78, p < 0.001). Bland-Altman analysis revealed poor agreement (bias = −15 mL/100 g/min, lower and upper limits of agreements = −16 and 45 mL/100 g/min, respectively) with a negative relationship. Accounting for the negative relationship, the width of the limits of agreement could be narrowed from 61 mL/100 g/min to 35 mL/100 g/min using regression-based limits of agreements. Although a high correlation between CBFASL and CBFPET was found, the agreement in absolute CBF values was not sufficient for ASL to be used interchangeably with 15O-water PET.

Serotonin transporter genotype modulates resting state and predator stress-induced amygdala perfusion in mice in a sex-dependent manner

The serotonin transporter (5-HTT) is a key molecule of serotoninergic neurotransmission and target of many anxiolytics and antidepressants. In humans, 5-HTT gene variants resulting in lower expression levels are associated with behavioral traits of anxiety. Furthermore, functional magnetic resonance imaging (fMRI) studies reported increased cerebral blood flow (CBF) during resting state (RS) and amygdala hyperreactivity. 5-HTT deficient mice as an established animal model for anxiety disorders seem to be well suited for investigating amygdala (re-)activity in an fMRI study. We investigated wildtype (5-HTT+/+), heterozygous (5-HTT+/-), and homozygous 5-HTT-knockout mice (5-HTT-/-) of both sexes in an ultra-high-field 17.6 Tesla magnetic resonance scanner. CBF was measured with continuous arterial spin labeling during RS, stimulation state (SS; with odor of rats as aversive stimulus), and post-stimulation state (PS). Subsequently, post mortem c-Fos immunohistochemistry elucidated neural activation on cellular level. The results showed that in reaction to the aversive odor CBF in total brain and amygdala of all mice significantly increased. In male 5-HTT+/+ mice amygdala RS CBF levels were found to be significantly lower than in 5-HTT+/- mice. From RS to SS 5-HTT+/+ amygdala perfusion significantly increased compared to both 5-HTT+/- and 5-HTT-/- mice. Perfusion level changes of male mice correlated with the density of c-Fos-immunoreactive cells in the amygdaloid nuclei. In female mice the perfusion was not modulated by the 5-Htt-genotype, but by estrous cycle stages. We conclude that amygdala reactivity is modulated by the 5-Htt genotype in males. In females, gonadal hormones have an impact which might have obscured genotype effects. Furthermore, our results demonstrate experimental support for the tonic model of 5-HTTLPR function.

Altered central pain processing in fibromyalgia-A multimodal neuroimaging case-control study using arterial spin labelling.

Fibromyalgia is characterized by chronic pain and a striking discrepancy between objective signs of tissue damage and severity of pain. Function and structural alterations in brain areas involved in pain processing may explain this feature. Previous case-control studies in fibromyalgia focused on acute pain processing using experimentally-evoked pain paradigms. Yet, these studies do not allow conclusions about chronic, stimulus-independent pain. Resting-state cerebral blood flow (rsCBF) acquired by arterial spin labelling (ASL) may be a more accurate marker for chronic pain. The objective was to integrate four different functional and structural neuroimaging markers to evaluate the neural correlate of chronic, stimulus-independent pain using a resting-state paradigm. In line with the pathophysiological concept of enhanced central pain processing we hypothesized that rsCBF is increased in fibromyalgia in areas involved in processing of acute pain. We performed an age matched case-control study of 32 female fibromyalgia patients and 32 pain-free controls and calculated group differences in rsCBF, resting state functional connectivity, grey matter volume and cortical thickness using whole-brain and region of interest analyses. We adjusted all analyses for depression and anxiety. As centrally acting drugs are likely to interfere with neuroimaging markers, we performed a subgroup analysis limited to patients not taking such drugs. We found no differences between cases and controls in rsCBF of the thalamus, the basal ganglia, the insula, the somatosensory cortex, the prefrontal cortex, the anterior cingulum and supplementary motor area as brain areas previously identified to be involved in acute processing in fibromyalgia. The results remained robust across all neuroimaging markers and when limiting the study population to patients not taking centrally acting drugs and matched controls. In conclusion, we found no evidence for functional or structural alterations in brain areas involved in acute pain processing in fibromyalgia that could reflect neural correlates of chronic stimulus-independent pain.

Changes in resting-state cerebral blood flow and its connectivity in patients with focal to bilateral tonic-clonic seizures

Arterial spin labeling (ASL) is an important tool for understanding cerebral perfusion in epilepsy patients. The aim of this study was to explore patterns of change in cerebral blood flow (CBF) and CBF connectivity in patients with focal to bilateral tonic-clonic seizures (FBTCS).High-resolution three-dimensional (3-D) T1-weighted and 3-D pseudo-continuous ASL magnetic resonance imaging (MRI) was collected from 32 patients with FBTCS and 16 healthy volunteers using a 3.0 T MRI scanner. Cerebral blood flow and its connectivity were compared between the FBTCS and control group. Correlation analysis was used to explore relationships of CBF and its connectivity changes with clinical parameters. Cerebral blood flow data of spatial standardization and normalization were used to improve statistical power.Patients with FBTCS exhibited increased CBF in the bilateral thalamus, caudate nucleus, olfactory cortex, and gyrus rectus, but decreased CBF in the bilateral supplementary motor areas (SMA) and middle cingulate cortex (MCC). Patients with FBTCS showed significant positive correlation between CBF and gray matter volume (GMV) in bilateral SMA and MCC. No significant correlations between CBF and clinical parameters were found among FBTCS patients. The anterior cingulate cortex (ACC) showed positive CBF connectivity with the bilateral SMA and MCC, and these CBF connectivity measures differed significantly between groups (cluster-level, FWE-corrected, P < 0.001).These findings suggest that patients with FBTCS have changes in cerebral CBF and CBF connectivity, which may relate to the underlying neuropathology of FBTCS.