Left Prefrontal White Matter Research Articles

Molecular hydrogen modulates brain glutamate/GABA-glutamine cycle in overweight humans.

We evaluated whether 12-week intake of molecular hydrogen (H2) in 5 overweight adults (3 women; age: 50.2 ±11.9 years, body mass index: 29.4 ±2.1 kg/m2) affects brain levels of the glutamate-glutamine-GABA cycle, critical amino acid neurotransmitters in the mechanism of neuronal activation during appetite regulation. A 1.5-T single-voxel proton magnetic resonance spectroscopy was used to assess the tissue concentrations of relevant metabolites. The mean glutamate and glutamate-plus-glutamine levels at the posterior cingulate gyrus decreased significantly during the study; this was accompanied by a significant drop in GABA levels at left prefrontal white matter, and glutathione levels at anterior cingulate gyrus. No changes in the brain metabolites were found in the comparable group of overweight individuals (n = 4, 2 women; age: 41.0 ±13.9, BMI 26.8 ±1.3 kg/m2) followed-up in the past without this treatment. We showed a possible hydrogen-driven upregulation of neurotransmitters involved in appetite stimulation leading to hunger suppression and weight loss. Further studies analyzing appetite-controlling metabolic pathways affected by H2 would require monitoring of additional biomarkers of satiation and satiety during different feeding regimens.

Correlations Among mRNA Expression Levels of ATP7A, Serum Ceruloplasmin Levels, and Neuronal Metabolism in Unmedicated Major Depressive Disorder.

BackgroundPrevious studies have found that elevated copper levels induce oxidation, which correlates with the occurrence of major depressive disorder (MDD). However, the mechanism of abnormal cerebral metabolism of MDD patients remains ambiguous. The main function of the enzyme ATPase copper-transporting alpha (ATP7A) is to transport copper across the membrane to retain copper homeostasis, which is closely associated with the onset of mental disorders and cognitive impairment. However, less is known regarding the association of ATP7A expression in MDD patients.MethodsA total of 31 MDD patients and 21 healthy controls were recruited in the present study. Proton magnetic resonance spectroscopy was used to assess the concentration levels of N-acetylaspartate, choline (Cho), and creatine (Cr) in brain regions of interest, including prefrontal white matter (PWM), anterior cingulate cortex (ACC), thalamus, lentiform nucleus, and cerebellum. The mRNA expression levels of ATP7A were measured using polymerase chain reaction (SYBR Green method). The correlations between mRNA expression levels of ATP7A and/or ceruloplasmin levels and neuronal biochemical metabolite ratio in the brain regions of interest were evaluated.ResultsThe decline in the mRNA expression levels of ATP7A and the increase in ceruloplasmin levels exhibited a significant correlation in MDD patients. In addition, negative correlations were noted between the decline in mRNA expression levels of ATP7A and the increased Cho/Cr ratios of the left PWM, right PWM, and right ACC in MDD patients. A positive correlation between elevated ceruloplasmin levels and increased Cho/Cr ratio of the left PWM was noted in MDD patients.ConclusionsThe findings suggested that the decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels induced oxidation that led to the disturbance of neuronal metabolism in the brain, which played important roles in the pathophysiology of MDD. The decline in the mRNA expression levels of ATP7A and the elevated ceruloplasmin levels affected neuronal membrane metabolic impairment in the left PWM, right PWM, and right ACC of MDD patients.

Relationship between white matter glucose metabolism and fractional anisotropy in healthy and schizophrenia subjects

Decreased fractional anisotropy and increased glucose utilization in the white matter have been reported in schizophrenia. These findings may be indicative of an inverse relationship between these measures of white matter integrity and metabolism. We used 18F-fluorodeoxyglucose positron emission tomography and diffusion-tensor imaging in 19 healthy and 25 schizophrenia subjects to assess and compare coterritorial correlation patterns between glucose utilization and fractional anisotropy on a voxel-by-voxel basis and across a range of automatically placed representative white matter regions of interest. We found a pattern of predominantly negative correlations between white matter metabolism and fractional anisotropy in both healthy and schizophrenia subjects. The overall strength of the relationship was attenuated in subjects with schizophrenia, who displayed significantly fewer and weaker correlations in all regions assessed with the exception of the corpus callosum. This attenuation was most prominent in the left prefrontal white matter and this region also best predicted the diagnosis of schizophrenia. There exists an inverse relationship between the measures of white matter integrity and metabolism, which may therefore be physiologically linked. In subjects with schizophrenia, hypermetabolism in the white matter may be a function of lower white matter integrity, with lower efficiency and increased energetic cost of task-related computations.

Altered biochemical metabolism and its lateralization in the cortico-striato-cerebellar circuit of unmedicated bipolar II depression

ObjectivesEvidence of the relationship between neurometabolic changes in the cortico-striato-cerebellar (CSC) circuit and bipolar disorder (BD) is still limited. To elucidate the pathogenesis of BD, we investigated the underlying neurometabolic changes and their effect on CSC lateralization circuits in unmedicated patients with bipolar II depression. MethodsForty unmedicated participants with bipolar II depression and forty healthy controls underwent proton magnetic resonance spectroscopy (1H-MRS). We obtained bilateral metabolic ratios of N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr in the prefrontal white matter (PWM), anterior cingulate cortex (ACC), basal ganglia (BG) and the cerebellum. Metabolic ratios were characterized using a laterality index (LI) for left-right asymmetry. ResultsOverall, aberrant lateralization in the CSC circuit was characteristic in patients with bipolar II depression. Patients with bipolar II depression showed significantly lower NAA/Cr ratios in the left PWM, right ACC, left BG and left cerebellum when compared with the healthy controls. For bipolar II depression, we found lower NAA/Cr LI in the PWM, BG, and cerebellum, higher NAA/Cr LI in the ACC, and higher Cho/Cr LI in the BG and cerebellum when compared to the standard value (1.0). For healthy controls, we found lower NAA/Cr LI only in the BG and higher Cho/Cr LI in the cerebellum when compared to 1.0. LimitationsAs a cross-sectional study with a small sample size, progressive changes and complex metabolic interactions with treatment were not observed. ConclusionsOur findings suggest that abnormal biochemical metabolism with aberrant lateralization in the CSC circuit may be an underlying pathophysiology of bipolar II depression.

Magnetic resonance spectroscopy in prefrontal white matter of bipolar II disorder and its relation with executive function

Objective To explore the magnetic resonance spectroscopy characteristics of prefrontal white matter in bipolar Ⅱ disorder and its relation with executive function. Methods Thirty bipolar Ⅱ disorder patients and twenty healthy controls were evaluated with Multi-Voxel proton magnetic resonance spectroscopy(1H-MRS)scans on prefrontal white matter to assess the N-acetyl-aspartate (NAA), Choline (Cho), Creatine (Cr) and myo-inositol (MI), and then the ratios of NAA/Cr, Cho/Cr, MI/Cr, NAA/Cho and NAA/Cho+ Cr were calculated.All subjects were assessed for executive function using the Wisconsin Card Sorting Test (WCST). Results NAA/Cr in right prefrontal white matter(1.43±0.26) and NAA/Cr, NAA/Cho, NAA/Cho+ Cr in left prefrontal white matter(separately1.40±0.29, 1.13(1.53, 0.24), 0.62±0.12) were lower than healthy controls(separately 1.58±0.18, 1.59, 0.23, 1.30(0.53±0.29), 0.71±0.08)(P<0.05). The correct trials and the number of categories of WCST in Bipolar Ⅱ disorder (separately 26.97±8.97, 3(6, 3)) were less than in healthy controls(separately 36.35±4.85, 5(3, 2)), and perseverative errors and random errors were more in patients(separately 12.77±5.73, 7(21, 5)) than healthy controls(separately 7.35±3.01, 4(13, 2)). NAA/Cho and NAA/Cho+ Cr in left prefrontal white matter were positively correlated with correct trials, number of categories, and negatively related with perseverative errors(P<0.05). Conclusions Bilateral prefrontal white matter fiber damage occurs to bipolar Ⅱ disorder. And left prefrontal white matter fiber damage in bipolar Ⅱ disorder may lead to executive impairment. Key words: Bipolar Ⅱ disorder; Magnetic resonance spectroscopy; Executive function; Frontal lobe

Analysis of ¹H-MRS in patients with depression after basal ganglia infarction

To investigate the metabolic changes on proton magnetic resonance spectroscopy (¹H-MRS) in patients with first left basal ganglia infarction and their relationship with depression. Twenty-two patients with first left basal ganglia infarction and 10 matched healthy controls were recruited in the study. Patients and controls underwent (1)H MRS scan and the spectrum of N-acetyl aspartic acid (NAA), choline (Cho) and creatinine (Cr) was recorded at the first week (D7) and 1 month after onset (M1), respectively. National Institutes of Health Stroke Scale (NIHSS), Ability of daily life (ADL), Hamilton Depression Scale (HAMD) were evaluated at D7, M1 and M6 after onset. The patients were classified into two groups: post-stroke depression (PSD) and non-post-stroke depression (NPSD) according to the result of HAMD.The differences of (1)H-MRS between these two groups were compared and their relationship with NIHSS and ADL was analyzed. Among 22 patients 10 were diagnosed as PSD and 12 were NPSD. Compared to controls, NAA/Cr was significantly lower and Cho/Cr was significantly higher (P <0.05)in left prefrontal white matter and left basal ganglia in patients with infarct. Patients with PSD showed a lower NAA/Cr and higher Cho/Cr than NPSD patients (P <0.05). At M1 after onset, NAA/Cr in the left prefrontal white matter was significantly correlated with NIHSS (r=-0.551, P =0.032), while Cho/Cr was correlated with ADL (r=0.682, P=0.005)in PSD patients. Metabolic changes shown on (1)H-MRS in patients with basal ganglia infarction may predict the occurrence of PSD.

Prefrontal and Occipital Asymmetry and Volume in Boys with Autism Spectrum Disorder

To examine prefrontal and occipital asymmetry (brain torque) in boys with autism spectrum disorder (ASD) and controls. A secondary aim was to study age-related changes in gray and white matter volume. Several studies have found atypical early cortical development in ASD. Atypical brain torque, defined as a greater-than-normal left prefrontal and right occipital asymmetry, has been found in some studies of children and adults with ASD. This configuration may be an early neural marker of ASD risk. We studied 24 right-handed boys with ASD and 27 typically developing right-handed boys, 7 to 15 years old, obtaining neuropsychological profiles and measuring prefrontal and occipital volumes on magnetic resonance images. Most participants had the expected rightward prefrontal and leftward occipital asymmetry, with no group differences in direction or degree of asymmetry. We found a trend toward larger prefrontal volume in the ASD group than in the controls. The controls also had a trend toward differences in age associations, correlating with total and left prefrontal white matter volumes. Our findings suggest that atypical brain torque may not be a neural signature of ASD, although our sample was limited to high-functioning, right-handed boys. Our results provide support for aberrant cortical development in ASD, continuing into adolescence, with prefrontal regions being disproportionally affected.

Prefrontal and Occipital Asymmetry and Volume in Children and Adolescents with Autism Spectrum Disorder (P03.129)

Objective: The purpose of this study was to examine prefrontal and occipital asymmetry (brain torque) in children and adolescents with autism spectrum disorder (ASD) compared to typically developing controls. A secondary aim was to examine age-related changes in gray and white matter volumes. Background ASD is a neurodevelopmental disorder, involving deficits in social functions and language and communication, accompanied by repetitive behaviors or restricted or unusual interests. Typical brain torque (R>L prefrontal, L>R occipital) has been shown to develop in utero and is thought to be related to functional laterality. Previous studies in ASD have demonstrated differences in cerebral asymmetry and early cortical development. Design/Methods: This study included 24 right-handed boys with ASD and 27 typically developing right-handed boys, 7-15 years old. Prefrontal and occipital volumes were measured on individual MRIs. Asymmetry quotients were calculated and volumes were examined proportional to total hemisphere volume. Correlations between age and gray and white matter volumes were examined in each group. Results: Most individuals had the expected rightward prefrontal and leftward occipital asymmetry, with no group differences in the number of individuals with these asymmetries or in the degree of asymmetry. We found a trend for larger prefrontal (gray+white) volume in the ASD group relative to controls (p=.053). Increasing age was associated with increases in total white matter (left r=.467, p=.014; right r=.410, p=.033) and left prefrontal white matter volume (r=.414, p=.032) in the typically developing, but not ASD group (p>.05). Conclusions: Our findings suggest that differences in brain torque may not underlie reported reduced functional lateralization in ASD, but studies directly examining this relationship need to be completed. Our results also provide further support for aberrant cortical development in ASD, likely occurring after birth and continuing into adolescence, with prefrontal regions being disproportionally affected. Supported by: National Institute on Deafness and Other Communication Disorders U19 DC 03610 (HTF). Disclosure: Dr. Knaus has nothing to disclose. Dr. Tager-Flusberg has nothing to disclose. Dr. Mock has nothing to disclose. Dr. Dauterive has nothing to disclose. Dr. Foundas has nothing to disclose.

The impact of a Dysbindin schizophrenia susceptibility variant on fiber tract integrity in healthy individuals: A TBSS-based diffusion tensor imaging study

Schizophrenia is a severe neuropsychiatric disorder with high heritability, though its exact etiopathogenesis is yet unknown. An increasing number of studies point to the importance of white matter anomalies in the pathophysiology of schizophrenia. While several studies have identified the impact of schizophrenia susceptibility gene variants on gray matter anatomy in both schizophrenia patients and healthy risk variant carriers, studies dealing with the impact of these gene variants on white matter integrity are still scarce. We here present a study on the effects of a Dysbindin schizophrenia susceptibility gene variant on fiber tract integrity in healthy young subjects. 101 subjects genotyped for Dysbindin-gene variant rs1018381, though without personal or first degree relative history of psychiatric disorders underwent diffusion tensor imaging (DTI), 83 of them were included in the final analysis. We used Tract-Based Spatial Statistics (TBSS) analysis to delineate the major fiber tracts. Carriers of the minor allele T of the rs1018381 in the Dysbindin gene showed two clusters of reduced fractional anisotropy (FA) values in the perihippocampal region of the right temporal lobe compared to homozygote carriers of the major allele C. Clusters of increased FA values in T-allele carriers were found in the left prefrontal white matter, the right fornix, the right midbrain area, the left callosal body, the left cerebellum and in proximity of the right superior medial gyrus. Dysbindin has been implicated in neurite outgrowth and morphology. Impairments in anatomic connectivity as found associated with the minor Dysbindin allele in our study may result in increased risk for schizophrenia due to altered fiber tracts.

Fractional Anisotropy Changes After Several Weeks of Daily Left High-Frequency Repetitive Transcranial Magnetic Stimulation of the Prefrontal Cortex to Treat Major Depression

As part of a sham controlled treatment trial using daily left repetitive transcranial magnetic stimulation (rTMS), brain changes associated with 4 to 6 weeks of treatment were examined using diffusion tensor imaging to noninvasively evaluate prefrontal white matter (WM) microstructure. A decrease in fractional anisotropy values of the left prefrontal WM could indicate damage to the region. Diffusion tensor imaging was performed before and after 4 to 6 weeks of daily rTMS treatments. Mean fractional anisotropy levels associated with active rTMS and sham rTMS for the right and left prefrontal WM were assessed. Adequate images were acquired for 8 participants (active n = 4, sham n = 4) before and after rTMS. A mean increase was found for the left prefrontal WM. The mixed model revealed a trend toward a significant treatment group × region interaction effect (P = 0.11). Furthermore, simple region effects (left prefrontal WM vs right prefrontal WM) were at a trend toward significance for difference after treatment within the active rTMS group (P = 0.07), but not within the sham rTMS group (P = 0.88). Repetitive transcranial magnetic stimulation resulted in no evidence of damage to WM on the side of stimulation. Diffusion tensor imaging may offer a unique modality to increase our understanding of mechanisms of action for rTMS.

Proton MRS in twin pairs discordant for schizophrenia

Proton magnetic resonance spectroscopy ((1)H MRS) neurometabolite abnormalities have been detected widely in subjects with and at risk for schizophrenia. We hypothesized that such abnormalities would be present both in patients with schizophrenia and in their unaffected twin siblings. We acquired magnetic resonance spectra (TR/TE=3000/30 ms) at voxels in the mesial prefrontal gray matter, left prefrontal white matter and left hippocampus in 14 twin pairs discordant for schizophrenia (2 monozygotic, 12 dizygotic), 13 healthy twin pairs (4 monozygotic, 9 dizygotic) and 1 additional unaffected co-twin of a schizophrenia proband. In the mesial prefrontal gray matter voxel, N-acetylaspartate (NAA), creatine+phosphocreatine (Cr), glycerophosphocholine+phosphocholine (Cho) and myo-inositol (mI) did not differ significantly between patients with schizophrenia, their unaffected co-twins or healthy controls. However, glutamate (Glu) was significantly lower in patients with schizophrenia (31%, percent difference) and unaffected co-twins (21%) than in healthy controls (collapsed across twin pairs). In the left hippocampus voxel, levels of NAA (23%), Cr (22%) and Cho (36%) were higher in schizophrenia patients compared with controls. Hippocampal NAA (25%), Cr (22%) and Cho (37%) were also significantly higher in patients than in their unaffected co-twins. Region-to-region differences in metabolite levels were also notable within all three diagnosis groups. These findings suggest that (1)H MRS neurometabolite abnormalities are present not only in patients with schizophrenia, but also in their unaffected co-twins. Thus, reduced mesial prefrontal cortical Glu and elevated hippocampal NAA, Cr and Cho may represent trait markers of schizophrenia risk and, when exacerbated, state markers of schizophrenia itself.

Brain Atrophy or Dystrophy in Schizophrenia: When Did It Happen?

B et al, 1 reporting on a quantitative magnetic resonance imaging investigation of 44 neuroleptic-treated schizophrenic patients and 29 healthy volunteers, found a decrease in volume of left and right amygdalahippocampal complex and a smaller volume of right and left prefrontal white matter in the schizophrenic group. These findings support and extend similar results by others from previous imaging and quantitative postmortem studies. 2-6 This study 1 also measured total cerebral and cerebrospinal fluid volume based on an outline of the dura on serial magnetic resonance imaging slices, excluding the brain stem and cerebellum. There was no significant difference between the schizophrenic cohort and controls in this measure of total cerebral volume, which may be considered to be equivalent to the measurement of head circumference. Many investigators consider that a reduction in the volume of the medial temporal lobe and other structures in schizophrenia represents a neurodevelopmental disorder, ie, a