Nicolas R. Bolo

Resting-State Brain Functional Connectivity Is Altered in Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD). Populations at risk for AD show altered brain activity in the default mode network (DMN) before cognitive dysfunction. We evaluated this brain pattern in T2DM patients. We compared T2DM patients (n = 10, age = 56 ± 2.2 years, fasting plasma glucose [FPG] = 8.4 ± 1.3 mmol/L, HbA1c = 7.5 ± 0.54%) with nondiabetic age-matched control subjects (n = 11, age = 54 ± 1.8 years, FPG = 4.8 ± 0.2 mmol/L) using resting-state functional magnetic resonance imaging to evaluate functional connectivity strength among DMN regions. We also evaluated hippocampal volume, cognition, and insulin sensitivity by homeostasis model assessment of insulin resistance (HOMA-IR). Control subjects showed stronger correlations versus T2DM patients in the DMN between the seed (posterior cingulate) and bilateral middle temporal gyrus (β = 0.67 vs. 0.43), the right inferior and left medial frontal gyri (β = 0.75 vs. 0.54), and the left thalamus (β = 0.59 vs. 0.37), respectively, with no group differences in cognition or hippocampal size. In T2DM patients, HOMA-IR was inversely correlated with functional connectivity in the right inferior frontal gyrus and precuneus. T2DM patients showed reduced functional connectivity in the DMN compared with control subjects, which was associated with insulin resistance in selected brain regions, but there were no group effects of brain structure or cognition.

Brain Pharmacokinetics and Tissue Distribution In Vivo of Fluvoxamine and Fluoxetine by Fluorine Magnetic Resonance Spectroscopy

This investigation of fluvoxamine and fluoxetine-norfluoxetine distributions in vivo at steady-state and of quantitative kinetics in brain and plasma after drug therapy interruption was performed by fluorine nuclear magnetic resonance spectroscopy (19F MRS), spectroscopic imaging (MRSI), and plasma HPLC on 12 subjects treated for depression. MRSI suggests a homogeneous distribution of 19F MRS visible fluvoxamine mainly in brain. Fluvoxamine steady-state brain concentrations (12 ± 5 μM; n = 13) and brain-to-plasma concentration ratios (10 ± 2; n = 12) were similar to those of combined fluoxetine-norfluoxetine (CF-norfluoxetine) (13 ± 6 μM; n = 4 and 10 ± 6; n = 4). Fluvoxamine brain elimination half-life (79 ± 24 hours; n = 4) was significantly shorter than that of CF-norfluoxetine (382 ± 48 hours; n = 2). Fluvoxamine brain-to-plasma-half-life-ratio was 2.2 ± 0.3 (n = 4), contrarily to CF-norfluoxetine (1.0 ± 0.3; n = 2). This study shows that quantitative pharmacokinetics in target organs by 19F MRS in vivo should prove useful for understanding and investigating outcome of treatment modifications and side effects.

Central effects of acamprosate: part 1. Acamprosate blocks the glutamate increase in the nucleus accumbens microdialysate in ethanol withdrawn rats.

One of the known behavioral actions of acamprosate is to decrease hypermotility during alcohol withdrawal. However, the mechanism of this effect remains unclear. In this study, the concentrations of excitatory and inhibitory amino acids were assayed by the microdialysis technique with OPA/BME precolumn derivatization and electrochemical detection in the nucleus accumbens of male Wistar rats which were either alcoholized by ethanol inhalation or simultaneously alcoholized and treated orally by acamprosate (400 mg/kg/day) for 4 weeks. Without treatment, extracellular glutamate increased during the withdrawal phase, while other amino acids tested (aspartate, arginine, taurine, alanine and GABA) remained stable. In contrast, the alcoholized rats treated with acamprosate failed to present the increase in glutamate during ethanol withdrawal, while other amino acids tested also remained stable. The observed glutamate increase could be responsible for the hyperexcitability observed during episodes of ethanol withdrawal. These results suggest that acamprosate is able to reduce the ethanol withdrawal syndrome by reducing the concentration of glutamate in the nucleus accumbens.

Brain Bioenergetics and Response to Triiodothyronine Augmentation in Major Depressive Disorder

BACKGROUND Low cerebral bioenergetic metabolism has been reported in subjects with major depressive disorder (MDD). Thyroid hormones have been shown to increase brain bioenergetic metabolism. We assessed whether changes in brain bioenergetics measured with phosphorus magnetic resonance spectroscopy ((31)P MRS) correlate with treatment outcome during augmentation treatment with triiodothyronine (T3) in MDD. METHODS Nineteen subjects meeting DSM-IV criteria for MDD who had previously failed to respond to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs received open label and prospective augmentation treatment with T3 for 4 weeks. We obtained (31)P MRS spectra before and after treatment from all MDD subjects and baseline (31)P MRS from nine normal control subjects matched for age and gender. RESULTS At baseline, depressed subjects had lower intracellular Mg(2+) compared with control subjects. Seven MDD subjects (38.9%) were treatment responders (>or= 50% improvement). Total nucleoside triphosphate (NTP), which primarily represents adenosine triphosphate (ATP), increased significantly in MDD subjects responding to T3 augmentation compared with treatment nonresponders. Phosphocreatine, which has a buffer role for ATP, decreased in treatment responders compared with nonresponders. CONCLUSIONS The antidepressant effect of thyroid hormone (T3) augmentation of SSRIs is correlated with significant changes in the brain bioenergetic metabolism. This seems to be a re-normalization of brain bioenergetics in treatment responders. Further studies will determine whether these findings can be generalized to other antidepressant treatments.

Cerebral white matter integrity and resting-state functional connectivity in middle-aged patients with type 2 diabetes.

Early detection of brain abnormalities at the preclinical stage can be useful for developing preventive interventions to abate cognitive decline. We examined whether middle-aged type 2 diabetic patients show reduced white matter integrity in fiber tracts important for cognition and whether this abnormality is related to preestablished altered resting-state functional connectivity in the default mode network (DMN). Diabetic and nondiabetic participants underwent diffusion tensor imaging, functional magnetic resonance imaging, and cognitive assessment. Multiple diffusion measures were calculated using streamline tractography, and correlations with DMN functional connectivity were determined. Diabetic patients showed lower fractional anisotropy (FA) (a measure of white matter integrity) in the cingulum bundle and uncinate fasciculus. Control subjects showed stronger functional connectivity than patients between the posterior cingulate and both left fusiform and medial frontal gyri. FA of the cingulum bundle was correlated with functional connectivity between the posterior cingulate and medial frontal gyrus for combined groups. Thus, middle-aged patients with type 2 diabetes show white matter abnormalities that correlate with disrupted functional connectivity in the DMN, suggesting that common mechanisms may underlie structural and functional connectivity. Detecting brain abnormalities in middle age enables implementation of therapies to slow progression of neuropathology.

Altered Prefrontal Glutamate–Glutamine–γ-Aminobutyric Acid Levels and Relation to Low Cognitive Performance and Depressive Symptoms in Type 1 Diabetes Mellitus

CONTEXT Neural substrates for low cognitive performance and depression, common long-term central nervous system-related changes in patients with type 1 diabetes mellitus, have not yet been studied. OBJECTIVE To investigate whether prefrontal glutamate levels are higher in patients with type 1 diabetes and whether an elevation is related to lower cognitive performance and depression. DESIGN Cross-sectional study. SETTING General clinical research center. PARTICIPANTS One hundred twenty-three patients with adult type 1 diabetes with varying degrees of lifetime glycemic control and 38 healthy participants. MAIN OUTCOME MEASURES With the use of proton magnetic resonance spectroscopy, prefrontal glutamate-glutamine-gamma-aminobutyric acid (Glx) levels were compared between patients and control subjects. Relationships between prefrontal Glx levels and cognitive function and between Glx levels and mild depressive symptoms were assessed in patients with type 1 diabetes. RESULTS Prefrontal Glx concentrations were 9.0% (0.742 mmol/L; P = .005) higher in adult patients with type 1 diabetes than in healthy control subjects. There were positive linear trends for the effects of lifetime glycemic control on prefrontal Glx levels (P for trend = .002). Cognitive performances in memory, executive function, and psychomotor speed were lower in patients (P = .003, .01, and <.001, respectively) than in control subjects. Higher prefrontal Glx concentrations in patients were associated with lower performance in assessment of global cognitive function (0.11 change in z score per 1-mmol/L increase in Glx) as well as with mild depression. CONCLUSIONS The high prefrontal glutamate levels documented in this study may play an important role in the genesis of the low cognitive performance and mild depression frequently observed in patients with type 1 diabetes. Therapeutic options that alter glutamatergic neurotransmission may be of benefit in treating central nervous system-related changes in patients with adult type 1 diabetes.

Brain Activation During Working Memory Is Altered in Patients With Type 1 Diabetes During Hypoglycemia

OBJECTIVE To investigate the effects of acute hypoglycemia on working memory and brain function in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Using blood oxygen level–dependent (BOLD) functional magnetic resonance imaging during euglycemic (5.0 mmol/L) and hypoglycemic (2.8 mmol/L) hyperinsulinemic clamps, we compared brain activation response to a working-memory task (WMT) in type 1 diabetic subjects (n = 16) with that in age-matched nondiabetic control subjects (n = 16). Behavioral performance was assessed by percent correct responses. RESULTS During euglycemia, the WMT activated the bilateral frontal and parietal cortices, insula, thalamus, and cerebellum in both groups. During hypoglycemia, activation decreased in both groups but remained 80% larger in type 1 diabetic versus control subjects (P < 0.05). In type 1 diabetic subjects, higher HbA1c was associated with lower activation in the right parahippocampal gyrus and amygdala (R2 = 0.45, P < 0.002). Deactivation of the default-mode network (DMN) also was seen in both groups during euglycemia. However, during hypoglycemia, type 1 diabetic patients deactivated the DMN 70% less than control subjects (P < 0.05). Behavioral performance did not differ between glycemic conditions or groups. CONCLUSIONS BOLD activation was increased and deactivation was decreased in type 1 diabetic versus control subjects during hypoglycemia. This higher level of brain activation required by type 1 diabetic subjects to attain the same level of cognitive performance as control subjects suggests reduced cerebral efficiency in type 1 diabetes.

Brain metabolite alterations in young adults at familial high risk for schizophrenia using proton magnetic resonance spectroscopy

BACKGROUND Proton magnetic resonance spectroscopy ((1)H MRS) enables in-vivo measurement of several relevant brain metabolites and has provided evidence of a range of neurochemical abnormalities in schizophrenia, especially in glutamate and N-acetyl-aspartate (NAA). While individuals at high familial risk for schizophrenia (HR) exhibit some neurobiological findings observed in the disorder, (1)H MRS findings and their clinical correlates are not well characterized in this population. METHODS We compared 23 adolescent and young adult offspring of schizophrenia patients with 24 age- and sex-matched healthy controls using (1)H MRS. We acquired multi-voxel, short TE (1)H MRS measurements at 1.5T and obtained metabolite concentrations of N-acetyl-aspartate (NAA), combined glutamate and glutamine (Glu+Gln) and choline-containing compounds (GPC+PC) for the left and right thalamus, anterior cingulate gyrus, and caudate. We also assessed the relationship between regional metabolite levels, clinical measures and brain volume in a subset of 16 high-risk and 15 control subjects. RESULTS Compared to healthy controls, high-risk subjects showed reductions in NAA levels in all three regions (thalamus, caudate, and anterior cingulate cortex), increases in Glu+Gln in the thalamus and caudate, and increases in GPC+PC in the anterior cingulate. In HR, thalamic Glu+Gln concentration was positively correlated and thalamic NAA inversely correlated with measures of schizotypy. Anterior cingulate GPC+PC and caudate Glu+Gln were significantly correlated with attenuated psychotic symptom severity. Anterior cingulate NAA was correlated with executive function. CONCLUSIONS Our data suggest the occurrence of metabolic alterations in young relatives of schizophrenia patients similar to those seen in patients with established illness. The observed correlations with cognitive deficits and psychosis-related psychopathology suggest that these metabolic measures may have value as biomarkers of risk for schizophrenia.

Central effects of acamprosate: part 2. Acamprosate modifies the brain in-vivo proton magnetic resonance spectrum in healthy young male volunteers.

Although acamprosate is a drug which is successfully used for therapy in maintaining alcohol abstinence following alcohol withdrawal in chronic alcoholism, little is understood about its mechanism of action in the central nervous system. Our objective was to assess the effects of acamprosate on the central nervous system in healthy subjects by dynamic proton magnetic resonance spectroscopy (MRS) measurements localized in brain tissue in vivo. Recordings were performed after intravenous administration of acamprosate or placebo to eight healthy male volunteers participating in a double-blind, randomized, cross-over, placebo-controlled study. The data were acquired using a spin-echo volume selective localized spectroscopy scheme on a 3-T whole body MRS system. Spectra obtained at baseline and at 20-min time intervals after the beginning of drug infusion were analyzed on the basis of five non-overlapping spectral integration regions. In the acamprosate-treated group, the median integral values in the regions for which N-acetylaspartate and glutamate are the main signal contributors showed decreases relative to placebo 20 min after the infusion began. Results suggest a central glutamatergic effect of acamprosate consistent with cerebral microdialysis glutamate measurements in vivo obtained from alcoholized rats treated with acamprosate (Part 1 of this study). This study is to our knowledge the first one describing a central effect of acamprosate in humans by MRS.

Regional Brain Activation during Hypoglycemia in Type 1 Diabetes

CONTEXT Mechanisms underlying the brain response to hypoglycemia are not well understood. OBJECTIVE Our objective was to determine the blood glucose level at which the hypothalamus and other brain regions are activated in response to hypoglycemia in type 1 diabetic patients and control subjects. DESIGN This was a cross-sectional study evaluating brain activity using functional magnetic resonance imaging in conjunction with a hyperinsulinemic hypoglycemic clamp to lower glucose from euglycemia (90 mg/dl) to hypoglycemia (50 mg/dl). SETTING The study was performed at the Brain Imaging Center in the McLean Hospital. STUDY PARTICIPANTS Seven type 1 diabetic patients between 18 and 50 yr old and six matched control subjects were included in the study. INTERVENTION Hyperinsulinemic hypoglycemic clamp was performed. MAIN OUTCOME MEASURES Blood glucose level at peak hypothalamic activation, amount of regional brain activity during hypoglycemia in both groups, and difference in regional brain activation between groups were calculated. RESULTS The hypothalamic region activates at 68 +/- 9 mg/dl in control subjects and 76 +/- 8 mg/dl in diabetic patients during hypoglycemia induction. Brainstem, anterior cingulate cortex, uncus, and putamen were activated in both groups (P < 0.001). Each group also activated unique brain areas not active in the other group. CONCLUSIONS This application of functional magnetic resonance imaging can be used to identify the glucose level at which the hypothalamus is triggered in response to hypoglycemia and whether this threshold differs across patient populations. This study suggests that a core network of brain regions is recruited during hypoglycemia in both diabetic patients and control subjects.