Cortical Mechanisms of Single-Pulse Transcranial Magnetic Stimulation in Migraine.

Single-pulse transcranial magnetic stimulation (sTMS) of the occipital cortex is an effective migraine treatment. However, its mechanism of action and cortical effects of sTMS in migraine are yet to be elucidated. Using calcium imaging and GCaMP-expressing mice, sTMS did not depolarise neurons and had no effect on vascular tone. Pre-treatment with sTMS, however, significantly affected some characteristics of the cortical spreading depression (CSD) wave, the correlate of migraine aura. sTMS inhibited spontaneous neuronal firing in the visual cortex in a dose-dependent manner and attenuated L-glutamate-evoked firing, but not in the presence of GABAA/B antagonists. In the CSD model, sTMS increased the CSD electrical threshold, but not in the presence of GABAA/B antagonists. We first report here that sTMS at intensities similar to those used in the treatment of migraine, unlike traditional sTMS applied in other neurological fields, does not excite cortical neurons but it reduces spontaneous cortical neuronal activity and suppresses the migraine aura biological substrate, potentially by interacting with GABAergic circuits.

Neurocognitive impairment and gray matter volume reduction in HIV-infected patients.

Although neuropsychological studies of human immunodeficiency virus (HIV)-infected patients have demonstrated heterogeneity in neurocognitive impairment and neuroimaging studies have reported diverse brain regions affected by HIV, it remains unclear whether individual differences in neurocognitive impairment are underpinned by their neural bases. Here, we investigated spatial distribution patterns of correlation between neurocognitive function and regional gray matter (GM) volume across patients with HIV. Thirty-one combination antiretroviral therapy-treated HIV-infected Japanese male patients and 33 age- and sex-matched healthy controls were included in the analysis after strict exclusion criteria, especially for substance use. Fifteen neurocognitive tests were used, and volumetric magnetic resonance imaging was performed. We used voxel-based morphometry to compare GM volume between groups and identify regional GM volumes that correlated with neurocognitive tests across patients. Using the Frascati criteria, 10 patients were diagnosed with asymptomatic neurocognitive impairment, while the others were not diagnosed with HIV-associated neurocognitive disorders. Patients showed a significantly lower performance in five neurocognitive tests as well as significantly reduced GM volume relative to controls, with volume-reduced regions spread diffusely across the whole brain. Different aspects of neurocognitive impairment (i.e., figural copy, finger tapping, and Pegboard) were associated with different GM regions. Our findings suggest a biological background constituting heterogeneity of neurocognitive impairment in HIV infection and support the clinical importance of considering individual differences for tailor-made medicine for people living with HIV.

Structural connectivity in adolescent synthetic cannabinoid users with and without ADHD.

Synthetic cannabinoids (SC) have become increasingly popular in the last few years, especially among adolescents. Given ADHD is overrepresented in patients with substance use across adolescents compared to the general population, the current study aims were two-fold: i) examine structural brain network topology in SC users compared to healthy controls and, ii) examine the influence of ADHD on network topology in SC users. Diffusion-weighted magnetic resonance imaging scans were acquired from 27 SC users (14 without ADHD and 13 with ADHD combined type) and 13 controls. Structural networks were examined using network-based statistic and connectomic analysis. We found that SC users without ADHD had significantly weaker connectivity compared to controls in bilateral hemispheres, most notably in edges connecting the left parietal and occipital regions. In contrast, SC users with ADHD showed stronger structural connectivity compared to controls. In addition, adolescent SC users with ADHD, but not without ADHD, displayed reduced network organization, indicated by lower clustering coefficient and modularity, suggesting that poor structural network segregation and preserved structural network integration. These results suggest that comorbidity of ADHD and substance dependence may show different structural connectivity alterations than substance use alone. Therefore, future connectivity studies in the substance use population should account for the presence of ADHD in their samples, which may be associated with disparate connectivity profiles.

Herring roe oil supplementation alters microglial cell gene expression and reduces peripheral inflammation after immune activation in a neonatal piglet model.

Neonatal brain development can be disrupted by infection that results in microglial cell activation and neuroinflammation. Studies indicate that polyunsaturated fatty acids (PUFAs) and their metabolites can resolve inflammation. It is not known if dietary PUFA increases lipid metabolites in brain or reduces neuroinflammation in neonates. We hypothesized that dietary PUFAs might suppress neuroinflammation by inhibiting pro-inflammatory cytokine over-production and promoting inflammatory resolution in the periphery and brain. Piglets were obtained on postnatal day (PD) 2 and randomly assigned to herring roe oil (HRO) or control (CON) diet. HRO was included at 2 g/kg powdered diet. HRO increased DHA levels in occipital lobe and the DHA to arachidonic acid (ARA) ratio in hippocampal tissue. HRO decreased ARA metabolites in occipital lobe. HRO failed to attenuate microglial pro-inflammatory cytokine production ex vivo. HRO did not affect fever or circulating resolvin D1 levels. HRO decreased circulating neutrophils and liver inflammatory gene expression, but increased resolution marker gene expression in liver post LPS. HRO upregulated CXCL16, TGFBR1, and C1QA in microglial cells. HRO supplementation exerted beneficial effects on inflammation in the periphery, but further studies are needed to evaluate the specific effects of omega-3 supplementation on microglial cell physiology in the neonate.

Early change of prefrontal theta cordance and occipital alpha asymmetry in the prediction of responses to antidepressants.

BACKGROUND: The study evaluated the effectiveness of EEG alpha 1, alpha 2 and theta power, along with prefrontal theta cordance (PFC), frontal and occipital alpha 1, alpha 2 asymmetry (FAA1/2, OAA1/2) at baseline and their changes at week 1 in predicting response to antidepressants. METHOD: Resting-state EEG data were recorded from 103 depressive patients that were treated in average for 5.1 ±â€¯0.9 weeks with SSRIs (n = 57) and SNRIs (n = 46). RESULTS: Fifty-five percent of patients (n = 56) responded to treatment (i.e.reduction of Montgomery-Åsberg Depression Rating Scale score ≥ 50%) and 45% (n = 47) of treated subjects did not reach positive treatment outcome. No differences in EEG baseline alpha and theta power or changes at week 1 for prefrontal, frontal, central, temporal and occipital regions were found between responders and non-responders. Both groups showed no differences at baseline PFC, FAA1/2 and OAA1/2 as well as change of FAA1/2 at week 1. The only parameters associated with treatment outcome were decrease of PFC in responders and increase of OAA1/2 at week 1 in non-responders. There was no influence of the used antidepressant classes on the results. The PFC change at week 1 (PFCC) (area under curve-AUC = 0.75) showed only a numerically higher predictive ability than OAA change in alpha 1 (OAA1C, AUC = 0.64)/alpha 2 (OAA2C, AUC = 0.63). A combined model, where OAA1C was added to PFCC (AUC = 0.79), did not significantly improve response prediction. CONCLUSION: Besides PFCC, we found that OAA1C/OAA2C might be another candidate for EEG predictors of antidepressant response.

Dose-dependent effects of the selective serotonin reuptake inhibitor citalopram: A combined SPECT and phMRI study.

BACKGROUND: Serotonin transporter blockers, like citalopram, dose-dependently bind to the serotonin transporter. Pharmacological magnetic resonance imaging (phMRI) can be used to non-invasively monitor effects of serotonergic medication. Although previous studies showed that phMRI can measure the effect of a single dose of serotoninergic medication, it is currently unclear whether it can also detect dose-dependent effects. AIMS: To investigate the dose-dependent phMRI response to citalopram and compared this with serotonin transporter occupancy, measured with single photon emission computed tomography (SPECT). METHODS: Forty-five healthy females were randomized to pre-treatment with placebo, a low (4 mg) or clinically standard (16 mg) oral citalopram dose. Prior to citalopram, and 3 h after, subjects underwent SPECT scanning. Subsequently, a phMRI scan with a citalopram challenge (7.5 mg intravenously) was conducted. Change in cerebral blood flow in response to the citalopram challenge was assessed in the thalamus and occipital cortex (control region). RESULTS: Citalopram dose-dependently affected serotonin transporter occupancy, as measured with SPECT. In addition, citalopram dose-dependently affected the phMRI response to intravenous citalopram in the thalamus (but not occipital cortex), but phMRI was less sensitive in distinguishing between groups than SPECT. Serotonin transporter occupancy showed a trend-significant correlation to thalamic cerebral blood flow change. CONCLUSION: These results suggest that phMRI likely suffers from higher variation than SPECT, but that these techniques probably also assess different functional aspects of the serotonergic synapse; therefore phMRI could complement positron emission tomography/SPECT for measuring effects of serotonergic medication.

Schizotypal Traits are Linked to Dopamine-Induced Striato-Cortical Decoupling: A Randomized Double-Blind Placebo-Controlled Study.

The dopamine hypothesis of schizophrenia implies that alterations in the dopamine system cause functional abnormalities in the brain that may converge to aberrant salience attribution and eventually lead to psychosis. Indeed, widespread brain disconnectivity across the psychotic spectrum has been revealed by resting-state functional magnetic resonance imaging (rs-fMRI). However, the dopaminergic involvement in intrinsic functional connectivity (iFC) and its putative relationship to the development of psychotic spectrum disorders remains partly unclear-in particular at the low-end of the psychosis continuum. Therefore, we investigated dopamine-induced changes in striatal iFC and their modulation by psychometrically assessed schizotypy. Our randomized, double-blind placebo-controlled study design included 54 healthy, right-handed male participants. Each participant was assessed with the Schizotypal Personality Questionnaire (SPQ) and underwent 10 minutes of rs-fMRI scanning. Participants then received either a placebo or 200 mg of L-DOPA, a dopamine precursor. We analyzed iFC of 6 striatal seeds that are known to evoke modulation of dopamine-related networks. The main effect of L-DOPA was a significant functional decoupling from the right ventral caudate to both occipital fusiform gyri. This dopamine-induced decoupling emerged primarily in participants with low SPQ scores, while participants with high positive SPQ scores showed decoupling indifferently of the L-DOPA challenge. Taken together, these findings demonstrate that schizotypal traits may be the result of dopamine-induced striato-occipital decoupling.

Decreased regional cerebral blood flow in patients with diphenylarsinic acid intoxication.

BACKGROUND AND PURPOSE: Diphenylarsinic acid (DPAA) intoxication caused by drinking contaminated well water was found in Kamisu, Japan. The symptoms indicated cerebellar-brainstem and temporo-occipital involvement. However, it remains unclear how it affects the human brain. To elucidate the effect of DPAA on the human brain, we analyzed cerebral blood flow (CBF) data after the drinking of DPAA-contaminated water was stopped and investigated the correlation between DPAA exposure level and CBF by single-photon emission computed tomography (CBF-SPECT). METHODS: The DPAA-exposed inhabitants (n = 78) were divided into 35 symptomatic and 43 asymptomatic subjects and compared with 38 healthy controls. The DPAA concentration in nails or hair and well water was measured using a high-performance liquid chromatography system and coupled plasma mass spectrometry after adequate extraction treatment. CBF-SPECT data, obtained within 1 year after the drinking of contaminated well water was stopped, were analyzed by statistical parametric mapping. We also examined the relationship between variations in CBF-SPECT signals and variations in DPAA concentrations in the hair or nails of the subjects. RESULTS: Compared with control subjects, CBF in symptomatic DPAA-exposed subjects was significantly lower in the occipital lobe, including the cuneus and inferior occipital gyri. The DPAA concentration in the nails or hair of subjects was inversely and significantly related to their CBF. CONCLUSION: These data suggest that CBF-SPECT may be useful as a clinical marker to infer the effect of accumulated DPAA on the brain.

Experimentally induced subclinical hypothyroidism causes decreased functional connectivity of the cuneus: A resting state fMRI study.

OBJECTIVE: The aim of this study was to experimentally evaluate the effects of subclinical mild hypothyroidism on brain network connectivity as determined by resting state fMRI (rsfMRI) which serves as a proxy for global changes in brain function. METHODS: Fifteen otherwise healthy patients with complete hypothyroidism under stable, long term levothyroxine substitution volunteered for the study. They reduced their pretest levothyroxine dosage by 30% for 52-56 days. Basally and after partial levothyroxine withdrawal, rsfMRI along with a neuropsychological analysis was performed. RsfMRI was subjected to graph-theory-based analysis to investigate whole-brain intrinsic functional connectivity. RESULTS: The desired subclinical hypothyroidism was achieved in all subjects. This was associated with a significant decrease in resting-state functional connectivity specifically in the cuneus (0.05 FWE corrected at cluster level) which was mainly caused by a weaker functional connectivity to the cerebellum and regions of the default mode network, i.e. the medial prefrontal cortex, the precuneus and the bilateral angular gyri. The decrease in cuneus connectivity was correlated to the increase in TSH serum levels. A working memory task showed a slightly longer reaction time and less accuracy after partial levothyroxine withdrawal. CONCLUSION: Even short-term partial levothyroxine partial withdrawal leads to deficits in working memory tasks and to a weaker integration of the cuneus within the default mode network.

Neurophysiological signals as predictive translational biomarkers for Alzheimer's disease treatment: effects of donepezil on neuronal network oscillations in TgF344-AD rats.

BACKGROUND: Translational research in Alzheimer's disease (AD) pathology provides evidence that accumulation of amyloid-ß and hyperphosphorylated tau, neuropathological hallmarks of AD, is associated with complex disturbances in synaptic and neuronal function leading to oscillatory abnormalities in the neuronal networks that support memory and cognition. Accordingly, our recent study on transgenic TgF344-AD rats modeling AD showed an age-dependent reduction of stimulation-induced oscillations in the hippocampus, and disrupted long-range connectivity together with enhanced neuronal excitability in the cortex, reflected in greatly increased expression of high-voltage spindles, an epileptic absence seizure-like activity. To better understand the translational value of observed oscillatory abnormalities in these rats, we examine here the effects of donepezil, an acetylcholine esterase inhibitor clinically approved for AD treatment. METHODS: Brainstem nucleus pontis oralis stimulation-induced hippocampal oscillations were recorded under urethane anesthesia in adult (6-month-old) and aged (12-month-old) TgF344-AD and wild-type rats. Spontaneous cortical activity was monitored in a cohort of freely behaving aged rats implanted with frontal and occipital cortical electroencephalography (EEG) electrodes. RESULTS: Subcutaneous administration of donepezil significantly augmented stimulation-induced hippocampal theta oscillation in aged wild-type rats and both adult and aged TgF344-AD rats, which have been previously shown to have diminished response to nucleus pontis oralis stimulation. Moreover, in adult TgF344-AD rats, donepezil also significantly increased theta phase-gamma amplitude coupling in the hippocampus during stimulation. However, neither of these effects were significantly changed in adult wild-type rats. Under freely behaving conditions, donepezil treatment had the opposite effect on cortical oscillatory connectivity in TgF344-AD and wild-type rats, and it reduced the occurrence of high-voltage spindle activity in TgF344-AD rats. CONCLUSIONS: Together, these results imply that pharmacologically enhancing cholinergic tone with donepezil could partially reverse oscillatory abnormalities in TgF344-AD rats, which is in line with its clinical effectiveness in AD patients. Therefore, our study suggests good translational opportunities for these neurophysiological signals recorded in TgF344-AD rats, and their application could be considered in drug discovery efforts for developing therapies with disease-modifying potential.

Longitudinal changes in the mismatch field evoked by an empathic voice reflect changes in the empathy quotient in autism spectrum disorder.

Autism spectrum disorders (ASDs) are neurodevelopmental conditions with impairments in social communication and interaction. Empathy is the ability to understand and share another person's inner life, and it is an essential process in social cognition, which is deficient in ASD. The mismatch field (MMF) has been used as a neurophysiological marker for the automatic detection of changes in auditory stimuli. In the present study, we focused on long-term changes in MMF evoked by an empathic voice and changes in the empathy quotient (EQ) in ASD during an 8-week clinical trial using oxytocin (OT). Ten males with ASD without intellectual disability participated in this pilot study. The results demonstrated a significant positive correlation between the change in the MMF amplitude in the auditory cortex (i.e., right banks of the superior sulcus) and the change in the EQ score during the 8-week clinical trial, whereas no significant change was observed in the MMF amplitude or EQ score after the administration period of OT. Although we cannot conclude that the observed relationships were caused by OT's effect or by natural changes, our results suggest that MMF evoked by social voice can be a state-dependent marker of empathic abilities in male adults with ASD.

Cue reactivity and opioid blockade in amphetamine dependence: A randomized, controlled fMRI study.

BACKGROUND: The opioid antagonist, naltrexone, has been shown to reduce the risk of relapse in amphetamine dependence, but the mechanisms behind this effect are not well understood. We aimed to investigate if naltrexone attenuates cue reactivity and craving in amphetamine dependence. METHODS: Forty men with severe, intravenous amphetamine dependence were randomized to one dose of naltrexone (50 mg) or placebo. In a BOLD fMRI cue reactivity paradigm, they were exposed to drug-related and neutral films and gave subjective ratings of craving after each film. Twenty-nine patients left data of sufficient quality to be included in the final analysis. RESULTS: The drug-related films elicited strong subjective craving and BOLD activations of the striatum, cingulate cortex, and occipito-temporal visual attention networks. Longer history of amphetamine use was associated with greater activations of the prefrontal cortex. Naltrexone as compared to placebo had no significant effects on brain activations or subjective ratings. CONCLUSION: Patients with severe stimulant use disorder exhibit strong neural cue reactivity, the patterns of which are modulated by duration of drug use. In this sample, we found no evidence for any effects of naltrexone on cue reactivity.

Altered Brain Dynamics in Patients With Type 1 Diabetes During Working Memory Processing.

It is now generally accepted that diabetes increases the risk for cognitive impairment, but the precise mechanisms are poorly understood. A critical problem in linking diabetes to cognitive impairment is that patients often have multiple comorbidities (e.g., obesity, hypertension) that have been independently linked to cognitive deficits. In the study reported here we focused on young adults with and without type 1 diabetes who were virtually free of such comorbidities. The two groups were matched on major health and demographic factors, and all participants completed a verbal working memory task during magnetoencephalographic brain imaging. We hypothesized that patients would have altered neural dynamics in verbal working memory processing and that these differences would directly relate to clinical disease measures. Accordingly, we found that patients had significantly stronger neural responses in the superior parietal cortices during memory encoding and significantly weaker activity in parietal-occipital regions during maintenance compared with control subjects. Moreover, disease duration and glycemic control were both significantly correlated with neural responses in various brain regions. In conclusion, young healthy adults with type 1 diabetes already have aberrant neural processing relative to their peers without diabetes, using compensatory responses to perform the task, and glucose management and duration may play a central role.

Focal segmental glomerulosclerosis in children complicated by posterior reversible encephalopathy syndrome.

An uncommon side effect of cyclosporine A (CsA) use is posterior reversible encephalopathy syndrome (PRES). PRES usually develops because of disturbed capacity of posterior cerebral blood flow to autoregulate an acute rise in blood pressure. We present the case of a 10-year-old girl who was previously diagnosed in our department with focal segmental glomerulosclerosis. She was treated with CsA and developed seizures, progressive loss of consciousness, and visual disturbance on the 7th day of treatment. Brain magnetic resonance imaging showed degeneration of white matter with diffuse demyelination in the parietal and posterior occipital lobes, consistent with the diagnosis of PRES. Cases of PRES reported in children are usually secondary to immunosuppressive therapy in oncological and haematological diseases. Our case is the fifth reported case of focal segmental glomerulosclerosis in children treated with CsA and complicated by PRES. Rapid recognition of PRES and stopping neurotoxic therapy early are essential for a good prognosis.

Light-Emitting Diode (LED) therapy improves occipital cortex damage by decreasing apoptosis and increasing BDNF-expressing cells in methanol-induced toxicity in rats.

Methanol-induced retinal toxicity, frequently associated with elevated free radicals and cell edema, is characterized by progressive retinal ganglion cell (RGC) death and vision loss. Previous studies investigated the effect of photomodulation on RGCs, but not the visual cortex. In this study, the effect of 670nm Light-Emitting Diode (LED) therapy on RGCs and visual cortex recovery was investigated in a seven-day methanol-induced retinal toxicity protocol in rats. Methanol administration showed a reduction in the number of RGCs, loss of neurons (neuronal nuclear antigen, NeuN+), activation of glial fibrillary acidic protein (GFAP+) expressing cells, suppression of brain-derived neurotrophic factor (BDNF+) positive cells, increase in apoptosis (caspase 3+) and enhancement of nitric oxide (NO) release in serum and brain. On the other hand, LED therapy significantly reduced RGC death, in comparison to the methanol group. In addition, the number of BDNF positive cells was significantly higher in the visual cortex of LED-treated group, in comparison to methanol-intoxicated and control groups. Moreover, LED therapy caused a significant decrease in cell death (caspase 3+ cells) and a significant reduction in the NO levels, both in serum and brain tissue, in comparison to methanol-intoxicated rats. Overall, LED therapy demonstrated a number of beneficial effects in decreasing oxidative stress and in functional recovery of RGCs and visual cortex. Our data suggest that LED therapy could be a potential condidate as a non-invasive approach for treatment of retinal damage, which needs further clinicl studies.

Methylmercury Causes Blood-Brain Barrier Damage in Rats via Upregulation of Vascular Endothelial Growth Factor Expression.

Clinical manifestations of methylmercury (MeHg) intoxication include cerebellar ataxia, concentric constriction of visual fields, and sensory and auditory disturbances. The symptoms depend on the site of MeHg damage, such as the cerebellum and occipital lobes. However, the underlying mechanism of MeHg-induced tissue vulnerability remains to be elucidated. In the present study, we used a rat model of subacute MeHg intoxication to investigate possible MeHg-induced blood-brain barrier (BBB) damage. The model was established by exposing the rats to 20-ppm MeHg for up to 4 weeks; the rats exhibited severe cerebellar pathological changes, although there were no significant differences in mercury content among the different brain regions. BBB damage in the cerebellum after MeHg exposure was confirmed based on extravasation of endogenous immunoglobulin G (IgG) and decreased expression of rat endothelial cell antigen-1. Furthermore, expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, increased markedly in the cerebellum and mildly in the occipital lobe following MeHg exposure. VEGF expression was detected mainly in astrocytes of the BBB. Intravenous administration of anti-VEGF neutralizing antibody mildly reduced the rate of hind-limb crossing signs observed in MeHg-exposed rats. In conclusion, we demonstrated for the first time that MeHg induces BBB damage via upregulation of VEGF expression at the BBB in vivo. Further studies are required in order to determine whether treatment targeted at VEGF can ameliorate MeHg-induced toxicity.

Encephalography Connectivity on Sources in Male Nonsmokers after Nicotine Administration during the Resting State.

We present an encephalography (EEG) connectivity study where 30 healthy male nonsmokers were randomly allocated either to a nicotine group (14 subjects, 7 mg of transdermal nicotine) or to a placebo group. EEG activity was recorded in an eyes-open (EO) and eyes-closed (EC) condition before and after drug administration. This is a reanalysis of a previous dataset. Through a source reconstruction procedure, we extracted 13 time series representing 13 sources belonging to a resting-state network. Here, we conducted connectivity analysis (renormalized partial directed coherence; rPDC) on sources, focusing on the frequency range of 8.5-18.4 Hz, subdivided into 3 frequency bands (α1, α2, and ß1) with the hypothesis that an increase in vigilance would modulate connectivity. Furthermore, a phase-amplitude coupling (mean resultant vector length; VL) analysis, was performed investigating whether an increase of vigilance would modulate phase-amplitude coupling. In the VL analysis we estimated the coupling of the phases of 3 low frequencies (α1, α2, and ß1), respectively, with the amplitude of high-frequency oscillations (30-40 Hz, low γ). With rPDC we found that during the EC condition, nicotine decreased feedback connectivity (from the precentral gyrus to precuneus, angular gyrus, cuneus and superior occipital gyrus) at 10.5-12.4 Hz. The VL analysis showed nicotine-induced increases in coupling at 10.5-18.4 Hz in the precuneus, cuneus and superior occipital gyrus during the EC condition. During the EO condition, no significant results were found in connectivity or phase-amplitude coupling measures at any frequency range. In conclusion, the results suggest that nicotine potentially increases the level of vigilance in the EC condition.

Long-term cognitive impairment of breast cancer patients after chemotherapy: A functional MRI study.

BACKGROUND: Chemotherapy, a prominent treatment for breast cancer (BC), can have detrimental side effects on the patient's cognitive functions including the executive function. However, the neurophysiological mechanism of the cognitive impairment remains unclear. OBJECTIVE: The purpose of this study is to explore long-term chemotherapy-related functional connectivity changes using fMRI and the relationship between the connectivity changes and the executive function impairment in breast cancer patients. METHODS: In this study, twenty-three breast cancer patients were treated with chemotherapy and twenty-six healthy subjects were recruited as the healthy control (HC) group. The functional connectivity of anterior cingulate cortex (ACC) was calculated from resting-state fMRI of the BC and control groups. The relationship between the functional connectivity of ACC and the executive function was further analyzed based on the patient' response time of the Stroop Interference Test. RESULTS: The results show that functional connectivity of ACC in the BC group is significantly lower than that in the control group. The correlation analysis within the BC group indicates that the functional connectivity of ACC was significantly correlated with the executive function. CONCLUSION: These findings provide evidence that the functional connectivity changes might be a pathophysiological basis for long-term chemotherapy-related cognitive dysfunction, along with executive function impairment in breast cancer patients.

Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla.

RATIONALE: Lithium is an effective treatment for bipolar disorder, but safety issues complicate its clinical use. The antioxidant drug, ebselen, may be a possible lithium-mimetic based on its ability to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium. OBJECTIVES: Our primary aim was to determine whether ebselen lowered levels of inositol in the human brain. We also assessed the effect of ebselen on other brain neurometabolites, including glutathione, glutamate, glutamine, and glutamate + glutamine (Glx) METHODS: Twenty healthy volunteers were tested on two occasions receiving either ebselen (3600 mg over 24 h) or identical placebo in a double-blind, random-order, crossover design. Two hours after the final dose of ebselen/placebo, participants underwent proton magnetic resonance spectroscopy ((1)H MRS) at 7 tesla (T) with voxels placed in the anterior cingulate and occipital cortex. Neurometabolite levels were calculated using an unsuppressed water signal as a reference and corrected for individual cerebrospinal fluid content in the voxel. RESULTS: Ebselen produced no effect on neurometabolite levels in the occipital cortex. In the anterior cingulate cortex, ebselen lowered concentrations of inositol (p = 0.028, Cohen's d = 0.60) as well as those of glutathione (p = 0.033, d = 0.58), glutamine (p = 0.024, d = 0.62), glutamate (p = 0.01, d = 0.73), and Glx (p = 0.001, d = 1.0). CONCLUSIONS: The study suggests that ebselen produces a functional inhibition of IMPase in the human brain. The effect of ebselen to lower glutamate is consistent with its reported ability to inhibit the enzyme, glutaminase. Ebselen may have potential as a repurposed treatment for bipolar disorder.

The effects of single nucleotide polymorphisms in glutamatergic neurotransmission genes on neural response to alcohol cues and craving.

The aim of the current study was to determine genotype effects of four single nucleotide polymorphisms (SNPs) in the genes of the N-Methyl-d-aspartate receptor (GRIN1, GRIN2A, GRIN2C) and kainate receptor (GRIK1), which have been previously associated with alcoholism, on behavior, neural cue-reactivity and drinking outcome. Eighty-six abstinent alcohol dependent patients were recruited from an in-patient setting. Neuropsychological tests, genotyping and functional magnetic resonance imaging (fMRI) were used to study genotype effects. GRIN2C risk allele carriers displayed increased alcohol cue-induced activation in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (dlPFC). Neural activation in the ACC positively correlated with craving for alcohol (r = 0.201, P = 0.032), whereas activation in the dlPFC showed a negative association (r = -0.215, P = 0.023). In addition, dlPFC activation predicted time to first relapse (HR = 2.701, 95%CI 1.244-5.864, P = 0.012). GRIK1 risk allele carriers showed increased cue-induced activation in the medial prefrontal (PFC) and orbitofrontal cortex (OFC) and in the lateral PFC and OFC. Activation in both clusters positively correlated with alcohol craving (rmedOFC, medPFC = 0.403, P = 0.001, rlatOFC, latPFC = 0.282, P = 0.008), and activation in the cluster that encompassed the medial OFC predicted time to first relapse (HR = 1.911, 95%CI 1.030-3.545, P = 0.040). Findings indicate that SNPs in the GRIN2C and GRIK1 genes are associated with altered cue-induced brain activation that is related to craving for alcohol and relapse risk.