Hippocampal and rostral anterior cingulate blood flow is associated with affective symptoms in chronic traumatic brain injury.

OBJECTIVE: The purpose of this study was to assess cerebral blood flow (CBF) and its association with self-reported symptoms in chronic traumatic brain injury (TBI). PARTICIPANTS: Sixteen participants with mild to severe TBI and persistent self-reported neurological symptoms, 6 to 72 months post-injury were included. For comparison, 16 age- and gender-matched healthy normal control participants were also included. MAIN MEASURES: Regional CBF and brain volume were assessed using pseudo-continuous Arterial Spin Labeling (PCASL) and T1-weighted data respectively. Cognitive function and self-reported symptoms were assessed in TBI participants using the national institutes of health (NIH) Toolbox Cognition Battery and Patient-Reported Outcome Measurement Information System respectively. Associations between CBF and cognitive function, symptoms were assessed. RESULTS: Global CBF and regional brain volumes were similar between groups, but region of interest (ROI) analysis revealed lower CBF bilaterally in the thalamus, hippocampus, left caudate, and left amygdala in the TBI group. Voxel-wise analysis revealed that CBF in the hippocampus, parahippocampus, rostral anterior cingulate, inferior frontal gyrus, and other temporal regions were negatively associated with self-reported anger, anxiety, and depression symptoms. Furthermore, region of interest (ROI) analysis revealed that hippocampal and rostral anterior cingulate CBF were negatively associated with symptoms of fatigue, anxiety, depression, and sleep issues. CONCLUSION: Regional CBF deficit was observed in the group with chronic TBI compared to the normal control (NC) group despite similar volume of cerebral structures. The observed negative correlation between regional CBF and affective symptoms suggests that CBF-targeted intervention may potentially improve affective symptoms and quality of life after TBI, which needs to be assessed in future studies.

Abnormal perfusion fluctuation and perfusion connectivity in bipolar disorder measured by dynamic arterial spin labeling.

OBJECTIVES: We sought to evaluate whether dynamic Arterial Spin Labeling (dASL), a novel quantitative technique robust to artifacts and noise that especially arise in inferior brain regions, could characterize neural substrates of BD pathology and symptoms. METHODS: Forty-five subjects (19 BD patients, 26 controls) were imaged using a dASL sequence. Maps of average perfusion, perfusion fluctuation, and perfusion connectivity with anterior cingulate cortex (ACC) were derived. Patient symptoms were quantified along four symptom dimensions determined using factor analysis of the subjects from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (BSNIP) study. Maps of the perfusion measures were compared between BD patients and controls and correlated with the symptom dimensions in the BD patients only by voxel-level and region-level analyses. RESULTS: BD patients exhibited (i) significantly increased perfusion fluctuations in the left fusiform and inferior temporal regions (P = .020, voxel-level corrected) and marginally increased perfusion fluctuations in the right temporal pole and inferior temporal regions (P = .063, cluster-level corrected), (ii) significantly increased perfusion connectivity between ACC and the occipitoparietal cortex (P = .050, cluster-level corrected). In BD patients, positive symptoms were negatively associated with ACC perfusion connectivity to the right orbitofrontal and superior frontal regions (P = .002, cluster-level corrected) and right orbitofrontal and inferior frontal regions (P = .023, cluster-level corrected). CONCLUSION: The abnormal perfusion fluctuations and connectivity alterations may underlie the mood fluctuations and cognitive and emotional dysregulation that characterize BD.

Anterior Cingulate Structure and Perfusion is Associated with Cerebrospinal Fluid Tau among Cognitively Normal Older Adult APOEɛ4 Carriers.

Evidence suggests the ɛ4 allele of the apolipoprotein E (APOE) gene may accelerate an age-related process of cortical thickening and cerebral blood flow (CBF) reduction in the anterior cingulate cortex (ACC). Although the neural basis of this association remains unclear, evidence suggests it might reflect early neurodegenerative processes. However, to date, associations between cerebrospinal fluid (CSF) biomarkers of neurodegeneration, such as CSF tau, and APOE-related alterations in ACC cortical thickness (CTH) and CBF have yet to be explored. The current study explored the interaction of CSF tau and APOE genotype (ɛ4+, ɛ4-) on FreeSurfer-derived CTH and arterial spin labeling MRI-measured resting CBF in the ACC (caudal ACC [cACC] and rostral ACC [rACC]) among a sample of 45 cognitively normal older adults. Secondary analyses also examined associations between APOE, CTH/CBF, and cognitive performance. In the cACC, higher CSF tau was associated with higher CTH and lower CBF in ɛ4+, whereas these relationships were not evident in ɛ4-. In the rACC, higher CSF tau was associated with higher CTH for both ɛ4+ and ɛ4-, and with lower CBF only in ɛ4+. Significant interactions of CSF tau and APOE on CTH/CBF were not observed in two posterior reference regions implicated in Alzheimer's disease. Secondary analyses revealed a negative relationship between cACC CTH and executive functioning in ɛ4+ and a positive relationship in ɛ4-. Findings suggest the presence of an ɛ4-related pattern of increased CTH and reduced CBF in the ACC that is associated with biomarkers of neurodegeneration and subtle decrements in cognition.

Hypoperfusion in the posterior cingulate cortex is associated with lower bone mass density in elderly women with osteopenia and Alzheimer's disease.

Accelerated bone loss is closely associated with Alzheimer's disease (AD), but the relationship between bone mineral density (BMD) and imaging markers of neurodegeneration remains uncertain. We examined the effect of low bone mass (osteopenia) on regional cerebral blood flow (rCBF) in patients with AD (n = 19) and non-demented aging (n = 12). We enrolled 31 female outpatients diagnosed with osteopenia (age ≥ 65 years) who had both a single-photon emission computed tomography brain scan and dual-energy X-ray absorptiometry bone scan taken at their initial investigation. We analyzed the relationship between osteopenia (-2.5 < T-score < -1) and rCBF in 62 cortical areas measured using the stereotactic extraction estimation analysis on single-photon emission computed tomography (SPECT) (mean Z-scores). We found that the mean Z-scores of 14 cerebral subregions, most of which are often affected early in AD, were significantly lower in the AD group than the non-demented group (P < .001). The age-stratified multivariate regression analysis showed that the decreased rCBF in the left posterior cingulate cortex (PCC) was an independent predictor of osteopenia (r = -0.395; P = .005). BMD and rCBF in the left PCC were significantly correlated in the overall population (r = -0.54; P = .001), as well as the AD group (r = -0.514; P = .02). These imaging data suggest that osteopenia may contribute to neurodegeneration of a brain network hub associated with AD.

Regional Cerebral Blood Flow in the Posterior Cingulate and Precuneus and the Entorhinal Cortical Atrophy Score Differentiate Mild Cognitive Impairment and Dementia Due to Alzheimer Disease.

BACKGROUND AND PURPOSE: Alzheimer disease is the most common degenerative dementia affecting humans and mild cognitive impairment is considered the forerunner of this devastating illness with variable progression. Differentiating between them has become all the more essential with the advent of disease-modifying medications. The aim of this study was to test the utility of the entorhinal cortical atrophy score in combination with quantitative CBF in the posterior cingulate and precuneus using arterial spin-labeling to differentiate mild cognitive impairment and early Alzheimer disease. MATERIALS AND METHODS: We analyzed MR imaging from a prospective data base of 3 age-matched groups: 21 cognitively healthy controls, 20 patients with mild cognitive impairment, and 19 patients with early Alzheimer disease. The highest entorhinal cortical atrophy score and an atlas-based measurement of CBF in the posterior cingulate and precuneus were estimated in these groups. Statistical comparison was performed among the groups for disease-prediction probability with these parameters independently and in combination using a binary logistic regression model. RESULTS: The entorhinal cortical atrophy score performed well in distinguishing AD from HC, with a predicted probability of .887 (area under the curve, P < .001). The mean CBF of the posterior cingulate and precuneus was also found to be a useful discriminator (area under the curve, 0.810, P = < .001). Combining the entorhinal cortical atrophy score and CBF was the best predictor (area under the curve, 0.957, P < .001). In distinguishing mild cognitive impairment and Alzheimer disease, entorhinal cortical atrophy also did well with an area under the curve of 0.838 (P < .001). However regional CBF was not useful in differentiating them (area under the curve = 0.589, P = .339). Entorhinal cortical atrophy scored poorly in distinguishing mild cognitive impairment from healthy controls (AUC = 0.571, P = .493), but CBF fared well, with an area under the curve of 0.776 (P = .002). CONCLUSIONS: Combining entorhinal cortical atrophy and regional CBF could be a potential imaging biomarker in distinguishing mild cognitive impairment and Alzheimer disease.

Resting Cerebral Blood Flow and Ethnic Differences in Heart Rate Variability: Links to Self-Reports of Affect and Affect Regulation.

Reduced high-frequency heart rate variability (HF-HRV) is associated with a greater risk for cardiovascular disease (CVD). Although African Americans (AA) are at greater risk for CVD, they show greater HF-HRV compared to European Americans (EA). Previous studies suggest that differences in the association between regional cerebral blood flow (CBF) and HF-HRV in AA and EA may explain this surprising pattern of findings, termed the Cardiovascular Conundrum. Here we pooled data from a total of n = 452 EA and n = 102 AA, investigating differences in the association between CBF in 8 regions of interest (ROI), including the cingulate (anterior, mid, posterior), insula (anterior, posterior), and amygdala (basolateral, centromedial, superfical), with HF-HRV, mean heart rate (HR) and their Coefficient of Variation (CoV). Bayesian statistics illustrate that CBF - in particular in the anterior cingulate cortex (ACC) - is positively associated with HF-HRV and CoV in EA, but negatively associated in AA. Exploring the association between HF-HRV and CBF with self-reports of affect and affect regulation showed some differences as a function of ethnicity. The association between greater habitual use of reappraisal only showed a positive correlation with HF-HRV in AA. Similar, greater suppression or non-expression of angry emotions was associated with greater HF-HRV whereas greater outward direction of anger was associated with lower HF-HRV in AA only. Given the importance of the ACC in emotion and emotion regulation, we suggest that increased HF-HRV may serve a compensatory role in AA. Implications from these findings and suggestions for future studies are discussed.

Effects of Home Photobiomodulation Treatments on Cognitive and Behavioral Function, Cerebral Perfusion, and Resting-State Functional Connectivity in Patients with Dementia: A Pilot Trial.

Objective: To examine the effects of transcranial and intranasal photobiomodulation (PBM) therapy, administered at home, in patients with dementia. Background: This study sought to replicate and build upon a previously published case series report describing improved cognitive function in five patients with mild-to-moderate dementia after 12 weeks of transcranial and intranasal near-infrared (NIR) PBM therapy. Materials and methods: Eight participants (mean age: 79.8 ± 5.8 years old) diagnosed with dementia by their physicians were randomized to 12 weeks of usual care (UC, n = 4) or home PBM treatments (n = 4). The NIR PBM treatments were administered by a study partner at home three times per week with the Vielight Neuro Gamma device. The participants were assessed with the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) subscale and the Neuropsychiatric Inventory (NPI) at baseline and 6 and 12 weeks, and with arterial spin-labeled perfusion magnetic resonance imaging (MRI) and resting-state functional MRI at baseline and 12 weeks. Results: At baseline, the UC and PBM groups did not differ demographically or clinically. However, after 12 weeks, there were improvements in ADAS-cog (group × time interaction: F1,6 = 16.35, p = 0.007) and NPI (group × time interaction: F1,6 = 7.52, p = 0.03), increased cerebral perfusion (group × time interaction: F1,6 = 8.46, p < 0.03), and increased connectivity between the posterior cingulate cortex and lateral parietal nodes within the default-mode network in the PBM group. Conclusions: Because PBM was well tolerated and associated with no adverse side effects, these results support the potential of PBM therapy as a viable home treatment for individuals with dementia.

Nightmare Severity Is Inversely Related to Frontal Brain Activity During Waking State Picture Viewing.

STUDY OBJECTIVES: Growing evidence suggests that nightmares have considerable adverse effects on waking behavior, possibly by increasing post-sleep negative emotions. Dysphoric reactions to nightmares are one component of nightmare severity for which the neural correlates are unknown. Here, we investigate possible neural correlates of nightmare severity in a sample of individuals who frequently recall nightmares. METHODS: Our principal measure of nightmare severity is nightmare distress as indexed by the Nightmare Distress Questionnaire (NDQ), and secondary measures are retrospective and prospective estimates of frequency of recalling dysphoric dreams (DD). We used high-resolution technetium 99m ethyl cysteinate dimer single photon emission computed tomography to assess regional cerebral blood flow (rCBF) while 18 individuals who were frequent nightmare recallers viewed negative and neutral pictures from the International Affective Picture System. We correlated rCBF with NDQ scores and DD recall frequency estimates. RESULTS: Negative correlations were observed between NDQ scores and rCBF during negative picture viewing in bilateral insula and anterior cingulate, right medial frontal gyrus, bilateral superior temporal gyrus, right inferior frontal and precentral gyri, and bilateral putamen. Retrospective DD recall correlated with rCBF activity primarily in regions overlapping those related to NDQ scores. Prospective DD recall was only weakly related to rCBF. Results for the neutral condition overlapped partially with those for the negative condition; in particular, NDQ and retrospective DD recall were related to rCBF in medial prefrontal and anterior cingulate gyri. CONCLUSIONS: Results point to a possible overlap in brain mechanisms involved in nightmare dysphoria (during sleep) and distress (during wakefulness) among individuals who frequently recall nightmares. They provide partial support for a neurocognitive model of nightmares. COMMENTARY: A commentary on this article appears in this issue on page 179.

Temporal dynamics of the pharmacological MRI response to subanaesthetic ketamine in healthy volunteers: A simultaneous EEG/fMRI study.

BACKGROUND: Pharmacological magnetic resonance imaging has been used to investigate the neural effects of subanaesthetic ketamine in healthy volunteers. However, the effect of ketamine has been modelled with a single time course and without consideration of physiological noise. AIMS: This study aimed to investigate ketamine-induced alterations in resting neural activity using conventional pharmacological magnetic resonance imaging analysis techniques with physiological noise correction, and a novel analysis utilising simultaneously recorded electroencephalography data. METHODS: Simultaneous electroencephalography/functional magnetic resonance imaging and physiological data were collected from 30 healthy male participants before and during a subanaesthetic intravenous ketamine infusion. RESULTS: Consistent with previous literature, we show widespread cortical blood-oxygen-level dependent signal increases and decreased blood-oxygen-level dependent signals in the subgenual anterior cingulate cortex following ketamine. However, the latter effect was attenuated by the inclusion of motion regressors and physiological correction in the model. In a novel analysis, we modelled the pharmacological magnetic resonance imaging response with the power time series of seven electroencephalography frequency bands. This showed evidence for distinct temporal time courses of neural responses to ketamine. No electroencephalography power time series correlated with decreased blood-oxygen-level dependent signal in the subgenual anterior cingulate cortex. CONCLUSIONS: We suggest the decrease in blood-oxygen-level dependent signals in the subgenual anterior cingulate cortex typically seen in the literature is the result of physiological noise, in particular cardiac pulsatility. Furthermore, modelling the pharmacological magnetic resonance imaging response with a single temporal model does not completely capture the full spectrum of neuronal dynamics. The use of electroencephalography regressors to model the response can increase confidence that the pharmacological magnetic resonance imaging is directly related to underlying neural activity.

Alterations in patients with major depressive disorder before and after electroconvulsive therapy measured by fractional amplitude of low-frequency fluctuations (fALFF).

BACKGROUND: Electroconvulsive therapy (ECT) is an important treatment option for patients with major depressive disorder (MDD). However, the mechanisms of ECT in MDD are still unclear. METHODS: Twenty-four patients with severe MDD and 14 healthy controls were enrolled in this study. Eight ECT sessions were conducted for MDD patients using brief-pulse square-wave signal at bitemporal locations. To investigate the regional cerebral blood flow in MDD patients before and after ECT treatments by resting-state functional magnetic resonance imaging (rs-fMRI), the patients were scanned twice (before the first ECT and after the eighth ECT) for data acquisition. Afterward, we adopted fractional amplitude of low-frequency fluctuations (fALFF) to assess the alterations of regional brain activity. RESULTS: Compared with healthy controls, the fALFF in the cerebellum lobe, parahippocampal gyrus, fusiform gyrus, anterior cingulate gyrus, and thalamus in MDD patients before ECT (pre-ECT) was significantly increased. In another comparison, the fALFF in the cerebellum anterior lobe, fusiform gyrus, insula, parahippocampal gyrus, middle frontal gyrus, and inferior frontal gyrus in pre-ECT patients was significantly greater than the post-ECT fALFF. LIMITATIONS: Only two rs-fMRI scans were conducted at predefined times: before the first and after the eighth ECT treatment. More scans during the ECT sessions would yield more information. In addition, the sample size in this study was limited. The number of control subjects was relatively small. A larger number of subjects would produce more robust findings. CONCLUSIONS: The fALFF of both healthy controls and post-ECT patients in cerebellum anterior lobe, fusiform gyrus, and parahippocampal gyrus is significantly lower than the fALFF of pre-ECT patients. This finding demonstrates that ECT treatment is effective on these brain areas in MDD patients.

The aging brain and cerebrovascular reactivity.

Cerebrovascular reactivity (CVR) is a measure of vascular response to a vasoactive stimulus, and can be used to assess the health of the brain vasculature. In this current study we used different analyses of BOLD fMRI responses to CO2 to provide a number of metrics including ramp and step CVR, speed of response and transfer function analysis (TFA). 51 healthy control volunteers between the ages of 18-85 (26 males) were recruited and scanned at 3T field strength. Atlases reflecting voxel-wise means and standard deviations were compiled to assess possible differences in these metrics between four age cohorts. Testing was carried out using an automated computer-controlled gas blender to induce hypercapnia in a step and ramp paradigm, and monitoring end-tidal partial pressures of CO2 (PETCO2) and O2 (PETO2). No significant differences were found for resting PETCO2 values between cohorts. Ramp CVR decreased significantly with age in white matter frontal regions comprising the ACA-MCA watershed area, a finding that may be indicative of age related changes. Similarly, TFA showed that gain was reduced in the left white matter ACA-MCA watershed area as well as the posterior and anterior cingulate cortex, and superior frontal gyrus in the oldest compared to youngest cohort. These findings, detailing changes in cerebrovascular regulation in the healthy aging brain should prove useful in mapping areas of dysregulated blood flow in individuals with vascular risk factors especially those at risk for developing vascular dementia.

[A case of body lateropulsion to the left in acute cerebral infarction of the right medial parietal lesion].

A 68-year-old right-handed woman with acute-onset inability to stand was admitted to our department. Although left hemiparesis was minor, the neurological examination on admission showed marked body lateropulsion (BL) to the left when she stood or stepped with eyes open and feet closed. Neither ataxia nor sensory disturbance was present. Brain MRI and 3D-CT angiography revealed infarction of the right posterior cingulate and the precuneus due to dissection of the right anterior cerebral artery. BL improved on day 10 and she was discharged without sequelae on day 26. BL caused by cerebral lesions is rare, and we should recognize that infarction of the posterior cingulate and/or the precuneus can cause BL.

Altered cerebral blood flow in the anterior cingulate cortex is associated with neuropathic pain.

OBJECTIVE: To assess the cerebral blood flow (CBF) in patients with diabetic neuropathic pain, and its changes after duloxetine therapy. METHODS: Using iodine-123-N-isopropyl-p-iodoamphetamine single-photon emission computed tomography (IMP-SPECT), we performed a cross-sectional study of 44 patients with diabetes, and compared CBF in those with (n = 24) and without neuropathic pain (n = 20). In patients with neuropathic pain, we also longitudinally assessed changes in CBF 3 months after treatment with duloxetine. RESULTS: IMP-SPECT with voxel-based analyses showed a significant increase in cerebral blood flow in the right anterior cingulate cortex and a decrease in the left ventral striatum in patients with neuropathic pain, compared with those without pain. After duloxetine treatment, volume of interest analyses revealed a decrease in cerebral blood flow in the anterior cingulate cortex in patients with significant pain relief but not in non-responders. Furthermore, voxel-based whole brain correlation analyses demonstrated that greater baseline CBF in the anterior cingulate cortex was associated with better pain relief on the numerical rating scale. CONCLUSIONS: Our results suggest that the development of neuropathic pain is associated with increased activity in the anterior cingulate cortex, and greater baseline activation of this region may predict treatment responsiveness to pharmacological intervention. TRIAL REGISTRATION NUMBER: UMIN000017130;Results.

Psychotic symptoms influence the development of anterior cingulate BOLD variability in 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11DS) is a neurodevelopmental disorder associated with a broad phenotype of clinical, cognitive and psychiatric features. Due to the very high prevalence of schizophrenia (30-40%), the investigation of psychotic symptoms in the syndrome is promising to reveal biomarkers for the development of psychosis, also in the general population. Since schizophrenia is seen as a disorder of the dynamic interactions between brain networks, we here investigated brain dynamics, assessed by the variability of blood oxygenation level dependent (BOLD) signals, in patients with psychotic symptoms. We included 28 patients with 22q11DS presenting higher positive psychotic symptoms, 29 patients with lower positive psychotic symptoms and 69 healthy controls between 10 and 30years old. To overcome limitations of mass-univariate approaches, we employed multivariate analysis, namely partial least squares correlation, combined with proper statistical testing, to analyze resting-state BOLD signal variability and its age-relationship in patients with positive psychotic symptoms. Our results revealed a missing positive age-relationship in the dorsal anterior cingulate cortex (dACC) in patients with higher positive psychotic symptoms, leading to globally lower variability in the dACC in those patients. Patients without positive psychotic symptoms and healthy controls had the same developmental trajectory in this region. Alterations of brain structure and function in the ACC have been previously reported in 22q11DS and linked to psychotic symptoms. The present results support the implication of this region in the development of psychotic symptoms and suggest aberrant BOLD signal variability development as a potential biomarker for psychosis.

Quantitative Changes in Cerebral Perfusion during Urinary Urgency in Women with Overactive Bladder.

PURPOSE: To quantitatively measure changes in cerebral perfusion in select regions of interest in the brain during urinary urgency in women with overactive bladder (OAB) using arterial spin labeling (ASL). METHODS: Twelve women with OAB and 10 controls underwent bladder filling and rated urinary urgency (scale 0-10). ASL fMRI scans were performed (1) in the low urgency state after voiding and (2) high urgency state after drinking oral fluids. Absolute regional cerebral blood flow (rCBF) in select regions of interest was compared between the low and high urgency states. RESULTS: There were no significant differences in rCBF between the low and high urgency states in the control group. In the OAB group, rCBF (mean ± SE, ml/100 g/min) increased by 10-14% from the low to the high urgency state in the right anterior cingulate cortex (ACC) (44.56 ± 0.59 versus 49.52 ± 1.49, p < 0.05), left ACC (49.29 ± 0.85 versus 54.02 ± 1.46, p < 0.05), and left insula (50.46 ± 1.72 versus 54.99 ± 1.09, p < 0.05). Whole-brain analysis identified additional areas of activation in the right insula, right dorsolateral prefrontal cortex, and pons/midbrain area. CONCLUSIONS: Urinary urgency is associated with quantitative increase in cerebral perfusion in regions of the brain associated with processing emotional response to discomfort.

Frontocingulate cerebral blood flow and cerebrovascular reactivity associated with antidepressant response in late-life depression.

BACKGROUND: Vascular pathology is common in late-life depression (LLD) and may contribute to alterations in cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). In turn, such hemodynamic deficits may adversely affect brain function and clinical course. The goal of this study was to examine whether altered cerebral hemodynamics in depressed elders predicted antidepressant response. METHODS: 21 depressed elders completed cranial 3T MRI, including a pseudo-continuous Arterial Spin Labeling (pcASL) acquisition on both room air and during a hypercapnia challenge. Participants then completed 12 weeks of open-label sertraline. Statistical analyses examined the relationship between regional normalized CBF and CVR values and change in Montgomery-Asberg Depression Rating Scale (MADRS) and tested for differences based on remission status. RESULTS: 10 participants remitted and 11 did not. After controlling for age and baseline MADRS, greater change in MADRS with treatment was associated with lower pre-treatment normalized CBF in the caudal anterior cingulate cortex (cACC) and lateral orbitofrontal cortex (OFC), as well as lower CVR with hypercapnia in the caudal medial frontal gyrus (cMFG). After controlling for age and baseline MADRS score, remitters exhibited lower CBF in the cACC and lower CVR in the cMFG. LIMITATIONS: Our sample was small, did not include a placebo arm, and we examined only specific regions of interest. CONCLUSIONS: Our findings suggest that increased perfusion of the OFC and the ACC is associated with a poor antidepressant response. They do not support that vascular pathology as measured by CBF and CVR negatively affects acute treatment outcomes.

Cholinergic enhancement increases regional cerebral blood flow to the posterior cingulate cortex in mild Alzheimer's disease.

AIM: The brain region that shows reductions in regional cerebral blood flow (rCBF) earliest is the posterior cingulate cortex (PCC), which is thought to have a relationship with cognitive function. We made a hypothesis that the PCC hypoperfusion is a result of cholinergic dysfunction and can be restored by cholinergic enhancement. This present longitudinal study aimed to detect the restoration of PCC rCBF in response to donepezil, an acetylcholine esterase inhibitor. METHODS: We evaluated rCBF changes in the PCC, precuneus and anterior cingulate cortex using perfusion single-photon emission computed tomography (SPECT), statistical analysis and region of interest analysis, prospectively. We allocated 36 patients with mild AD to either the responder or non-responder groups based on changes in Mini-Mental State Examination scores. The patients were followed up for 18 months. RESULTS: The PCC rCBF significantly increased in responders after 6 months of donepezil therapy. Statistical maps at baseline showed a typical decreased pattern of mild AD and obvious rCBF restoration in the bilateral PCC at 6 months in responders. Changes in Mini-Mental State Examination scores and the AD assessment scale cognitive scores significantly correlated with rCBF changes in the PCC of responders. CONCLUSIONS: Cholinergic enhancement restored PCC rCBF under the three conditions of mild AD, responders and short follow-up interval, and that increase correlated with improved cognitive function. These findings support our hypothesis that PCC rCBF reflects cholinergic function in AD patients. Geriatr Gerontol Int 2017; 17: 951-958.

Altered Glutamate and Regional Cerebral Blood Flow Levels in Schizophrenia: A 1H-MRS and pCASL study.

The neurobiology of schizophrenia (SZ) may be altered in older versus younger adults with SZ, as less frequent episodes of symptom exacerbation and increased sensitivity to medications are observed in older age. The goal of this study was to examine the effect of age and diagnosis on glutamate and cerebral blood flow (rCBF) in adults with SZ and healthy controls. Young and older adults with SZ and healthy controls were recruited to participate in this study. Participants completed a neuropsychological battery and neuroimaging that included optimized magnetic resonance spectroscopy to measure anterior cingulate (AC) glutamate (Glu) and glutamine (Gln) and arterial spin labeling evaluation for rCBF. Regression analyses revealed significant effects of age with Glu, Gln, Gln/Glu, and AC white matter (WM) rCBF. Glu and WM rCBF decreased linearly with age while Gln and Gln/Glu increased linearly with age. Glu was lower in adults with SZ compared with healthy controls and in older adults versus younger adults but there was no interaction. Glu and WM rCBF were correlated with the UCSD Performance-Based Skills Assessment (UPSA) and processing speed, and the correlations were stronger in the SZ group. In the largest sample to date, lower Glu and elevated Gln/Glu levels were observed in adults with SZ and in older subjects. Contrary to expectation, these results do not show evidence of accelerated Glu aging in the anterior cingulate region in SZ compared with healthy controls.

Increased cerebral blood flow among adolescents with bipolar disorder at rest is reduced following acute aerobic exercise.

OBJECTIVE: Cerebral blood flow (CBF) is altered in mood disorders but has not been examined among adolescents with bipolar disorder (BD). Similarly, little is known about the acute neurophysiologic effects of aerobic exercise in BD. We therefore compared CBF between adolescents with and without BD at rest and acutely following a single exercise session. METHODS: Thirty-one adolescents with BD and 20 age and sex-matched controls participated in this study. CBF magnetic resonance images (MRI) were acquired using arterial spin labeling at a baseline as well as 15 and 45min after a single 20-min session of recumbent cycling. Voxel-based CBF analyses compared groups at baseline and after exercise. Clinical, body mass index (BMI) and exercise-induced feelings inventory (EFI) data were examined for their influence on CBF findings. RESULTS: Baseline CBF was increased in medial frontal and middle cingulate regions in BD compared to controls. Analysis of the acute CBF changes revealed pronounced exercise-related decreases in CBF in BD. Exercise-related feelings of exhaustion were associated with CBF changes in frontal but not parietal regions. DISCUSSION: A single bout of moderate-intensity aerobic exercise reduced regional CBF to a greater extent in BD compared to controls; these time dependent CBF responses were associated with exercise-induced feelings of exhaustion.

Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial.

IMPORTANCE: Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. OBJECTIVES: To determine whether the effects of methylphenidate on the dopaminergic system are modified by age and to test the hypothesis that methylphenidate treatment of young but not adult patients with ADHD induces lasting effects on the cerebral blood flow response to dopamine challenge, a noninvasive probe for dopamine function. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial (Effects of Psychotropic Drugs on Developing Brain-Methylphenidate) among ADHD referral centers in the greater Amsterdam area in the Netherlands between June 1, 2011, and June 15, 2015. Additional inclusion criteria were male sex, age 10 to 12 years or 23 to 40 years, and stimulant treatment-naive status. INTERVENTIONS: Treatment with either methylphenidate or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES: Change in the cerebral blood flow response to an acute challenge with methylphenidate, noninvasively assessed using pharmacological magnetic resonance imaging, between baseline and 1 week after treatment. Data were analyzed using intent-to-treat analyses. RESULTS: Among 131 individuals screened for eligibility, 99 patients met DSM-IV criteria for ADHD, and 50 participants were randomized to receive methylphenidate and 49 to placebo. Sixteen weeks of methylphenidate treatment increased the cerebral blood flow response to methylphenidate within the thalamus (mean difference, 6.5; 95% CI, 0.4-12.6; P = .04) of children aged 10 to 12 years old but not in adults or in the placebo group. In the striatum, the methylphenidate condition differed significantly from placebo in children but not in adults (mean difference, 7.7; 95% CI, 0.7-14.8; P = .03). CONCLUSIONS AND RELEVANCE: We confirm preclinical data and demonstrate age-dependent effects of methylphenidate treatment on human extracellular dopamine striatal-thalamic circuitry. Given its societal relevance, these data warrant replication in larger groups with longer follow-up. TRIAL REGISTRATION: identifier: NL34509.000.10 and trialregister.nl identifier: NTR3103.