双相抑郁患者前额叶和前扣带回皮质氢质子波谱研究

目的:研究双相抑郁患者前额叶皮质、前扣带回皮质代谢物的相对含量。方法:对30例未服药双相抑郁患者和30名健康志愿者的前额叶皮质、前扣带回皮质进行氢质子波谱(1H-MRS)扫描,双相抑郁患者经6周药物治疗后再次做1H-MRS扫描,检测N-乙酰天门冬氨酸(NAA)、胆碱(Cho)、谷氨酸复合物(Glx)、肌酸(Cr)4种代谢物。结果:双相抑郁组左侧前额叶皮质、双侧前扣带回皮质NAA/Cr值均显著低于正常对照组(P<0.05),Cho/Cr值、Glx/Cr值均显著高于正常对照组(P<0.05),双相抑郁组右侧前额叶皮质NAA/Cr、Cho/Cr、Glx/Cr值两组比较差异无统计学意义(P>0.05)。经药物治疗后,左侧前额叶皮质、双侧前扣带回皮质NAA/Cr值较治疗前升高,Cho/Cr值、Glx/Cr值较治疗前降低,差异有统计学意义(P<0.05)。结论:前额叶和前扣带回皮质NAA、Cho、Glx含量的改变与双相抑郁的发生和药物的疗效有关。     

Quantitative proton magnetic resonance spectroscopy detects abnormalities in dorsolateral prefrontal cortex and motor cortex of patients with frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease of the frontal and temporal neocortex. The single most common pathology underlying FTLD is neuronal degeneration with ubiquitin-positive but tau-negative inclusions consisting of Tar DNA binding proteins (TDP-43). Inclusions containing TDP-43 in neurons are also the most common pathology underlying motor neuron disease (MND). The present study tested the hypothesis that abnormal metabolite patterns within the dorsolateral prefrontal cortex (DLPFC) as well as the motor cortex (MC) may be observed in FTLD patients without motor disorders, using proton magnetic resonance spectroscopy (¹H MRS). Twenty-six FTLD patients with cognitive damage and ten controls underwent multivoxel ¹H MRS. Absolute concentrations of N-acetyl aspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI) were measured from the DLPFC, the MC and the parietal cortex (PC, an internal control). Statistical analyses were performed for group differences between FTLD patients and controls. Comparisons were also made across brain regions (PC and DLPFC; PC and MC) within FTLD patients. Significant reductions in NAA and Cr along with increased Cho and mI were observed in the DLPFC of FTLD patients compared to controls. Significantly lower NAA and higher Cho were also observed in the MCs of patients as compared to controls. Within the FTLD patients, both the MC and the DLPFC exhibited significantly decreased NAA and elevated Cho compared to the PC. However, only the DLPFC had significantly lower Cr and higher mI. Abnormal metabolite pattern from the MC supports the hypothesis that FTLD and MND may be closely linked.     

有无遗传史的强迫症患者前额叶磁共振质子波谱对照研究

目的 探讨有无遗传史强迫症患者前额叶神经代谢物的变化.方法 采用磁共振质子波谱技术对有遗传史强迫症组(10例)、无遗传史强迫症组(14例)和对照组(12例)的内侧前额叶皮质N-乙酰天冬氨酸(NAA)、肌酸(Cr)和胆碱复合物(Cho)的代谢物含量进行对照研究.结果 有遗传史强迫症组的NAA值(46±8)和NAA/Cr值(1.59±0.24)分别高于对照组的NAA值(37±7)(方差分析LSD法校正,P=0.024)和NAA/Cr值(1.31±0. 21)(方差分析LSD法校正,P=0.006);有遗传史强迫症组的NAA值也高于无遗传史强迫症组的NAA值(37±10)(方差分析LSD法校正,P=0.021);无遗传史强迫症组与对照组相比,NAA/Cr值可见增加趋势(方差分析LSD法校正,P=0.066).结论 有遗传史强迫症患者的神经代谢物NAA与对照组和无遗传史强迫症患者相比在内侧前额叶皮质明显升高.     

双相抑郁患者前额叶及海马磁共振质子波谱成像研究

目的探讨双相抑郁患者前额叶及海马磁共振质子波谱(proton magnetic resonance spectroscopy,1H-MRS)的代谢物变化特点,为其神经生物学研究提供线索。方法应用磁共振质子波谱成像技术检测26例双相抑郁患者(患者组)和26例单相抑郁患者及13例健康志愿者(对照组)双侧前额叶白质、前扣带回皮质、海马N-乙酰天门冬氨酸(N-Acetylaspartate,NAA)、胆碱(choline,Cho)、肌酸(creatine,Cr)3种代谢物,以Cr为参照物,分别计算双侧NAA/Cr和Cho/Cr比值。采用SPSS 13.0进行统计处理。结果患者组左侧前额叶白质NAA/Cr(1.65±0.31)低于对照组(2.37±0.36),左侧前额叶白质Cho/Cr(1.35±0.27)低于对照组(1.65±0.21),差异有统计学意义(P<0.05);右侧前额叶白质NAA/Cr、Cho/Cr值与正常对照组差异无统计学意义;患者组双侧前扣带回NAA/Cr、Cho/Cr值与正常对照组差异无统计学意义;患者组双侧海马NAA/Cr、Cho/Cr值与正常对照组差异无统计学意义;患者组与单相抑郁组的双侧额叶白质、双侧前扣带回皮质、双侧海马NAA/Cr、Cho/Cr值差异均无统计学意义。结论双相抑郁患者可能存在左侧前额叶神经元功能下降和膜磷脂代谢异常,其代谢物特点存在偏侧化。     

Neurochemical metabolites in the medial prefrontal cortex in bipolar disorder A proton magnetic resonance spectroscopy study

The aim of this study was to investigate proton magnetic resonance spectroscopy metabolite values in the medial prefrontal cortex of individuals with euthymic bipolar disorder. The subjects consisted of 15 patients with euthymic bipolar disorder type Ⅰ and 15 healthy controls. We performed proton magnetic resonance spectroscopy of the bilateral medial prefrontal cortex and measured levels of N-acetyl aspartate, choline and creatine. Levels of these three metabolites in the medial prefrontal cortex were found to be lower in patients with bipolar disorder compared with healthy controls. A positive correlation was found between illness duration and choline levels in the right medial prefrontal cortex. Our study suggests that during the euthymic period, there are abnormalities in cellular energy and membrane phospholipid metabolism in the medial prefrontal cortex, and that this may impair neuronal activity and integrity.     

Myelin staining of deep white matter in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and unipolar major depression

The recreational drug MDMA (3,4, methylenedioxymethamphetamine; sold under the street name of Ecstasy) is toxic to serotonergic axons in some animal models of MDMA administration. In humans, MDMA use is associated with alterations in markers of brain function that are pronounced in occipital cortex. Among neuroimaging methods, magnetic resonance spectroscopy (MRS) studies of brain metabolites N-acetylaspartate (NAA) and myoinositol (MI) at a field strength of 1.5 Tesla (T) reveal inconsistent results in MDMA users. Because higher field strength proton MRS has theoretical advantages over lower field strengths, we used proton MRS at 4.0 T to study absolute concentrations of occipital cortical NAA and MI in a cohort of moderate MDMA users (n=9) versus non-MDMA using (n=7) controls. Mean NAA in non-MDMA users was 10.47 mM (+/-2.51), versus 9.83 mM (+/-1.94) in MDMA users. Mean MI in non-MDMA users was 7.43 mM (+/-.68), versus 6.57 mM (+/-1.59) in MDMA users. There were no statistical differences in absolute metabolite levels for NAA and MI in occipital cortex of MDMA users and controls. These findings are not supportive of MDMA-induced alterations in NAA or MI levels in this small sample of moderate MDMA users. Limitations to this study suggest caution in the interpretation of these results.     

抑郁症患者前额叶、海马磁共振质子波谱成像的研究

目的探讨抑郁症患者前额叶、海马的磁共振质子波谱(1H-MRS)变化特点。方法应用1H-MRS成像技术检测26例抑郁症患者(抑郁症组)和20名健康对照者(对照组)的前额叶、海马N-乙酰天门冬氨酸(NAA)、胆碱(Cho)、肌酸(Cr)3种代谢物,计算NAA/Cr和Cho/Cr比值。以抑郁症组年龄的中位数(38.5岁)为界将抑郁症组和对照组分为低年龄组[(28±7)岁,14例;(22±6)岁,9名]与高年龄组[(54±9)岁,12例;(53±7)岁,11名]。按病程分为首次发病组(19例,以下简称首发组)和复发组(7例)。采用方差分析进行统计比较。结果高年龄组患者左侧前额叶Cho/Cr(1.60±0.45)×10-6高于对照组(1.28±0.20)×10-6,差异有统计学意义(P<0.05);低年龄组患者右侧前额叶Cho/Cr(1.74±0.51)×10-6高于对照组(1.22±0.40)×10-6,差异有统计学意义(P<0.01)。高年龄组患者左侧海马NAA/Cr(1.16±0.31)×10-6低于对照组(2.21±0.83)×10-6,差异有统计学意义(P<0.01);低年龄组患者左侧海马Cho/Cr(1.54±0.44)×10-6高于对照组(1.08±0.35)×10-6,差异有统计学意义(P<0.05)。首发组患者左侧前额叶Cho/Cr(1.57±0.42)×10-6高于对照组(1.26±0.21)×10-6,复发组患者右侧前额叶Cho/Cr(1.77±0.50)×10-6高于对照组(1.29±0.32)×10-6,差异均有统计学意义(P均<0.01)。首发组患者左侧海马NAA/Cr(1.19±0.26)×10-6及复发组患者左侧海马NAA/Cr(1.10±0.29)×10-6均低于对照组(1.87±0.81)×10-6,复发组患者右侧海马Cho/Cr(2.13±0.51)×10-6高于对照组(1.51±0.52)×10-6,差异均有统计学意义(P均<0.01)。结论抑郁症患者可能存在前额叶、左侧海马细胞膜代谢异常,高年龄抑郁症患者的左侧海马神经元活力下降。     

抑郁症对海马及背外侧前额叶皮质神经元变与1HMRS表现及明尼苏达多项个性测量的相关性

Background and Purpose The present study was undertaken to elucidate neuro-structural and neuro-chemical characteristics of hippocampi and dorsolateral prefrontal cortex in patients with depressive disorder by using 1H-MRS and to study the association between 1H-MRS and Minnesota Mutiphasic Personality Inventory-2 in relation to the severity of the depression.. Methods Magnetic resonance imaging and 1H-MRS were performed on 33 patients with depressive disorder and age-18 and gender-matched healthy controls. Minnesota Mutiphasic Personality Inventory-2 test was performed on all depressive subjects and control subjects. Results Magnetic resonance imaging and 1H-MRS examinations showed widened sulcus and cisterns as well as the absence of abnormal signal in depressive patients. In addition, the N-acetyl aspartate/total creatine ratios in the bilateral hippocampi and dorsolateral prefrontal cortex were significantly lower in depressive patients than in the control subjects (P<0.01). In contrast, the choline-containing compounds/total creatine ratios in dorsolateral prefrontal cortex were remarkably higher in depressive patients than in the control subjects (Left: P<0.01, Right: P<0.01), the ratios of which were also significantly positively correlated with the depression scores of the patients assessed by Minnesota Mutiphasic Personality Inventory-2 scale (Right: r = 0.8787, Left: r = 0.9347). Conclusions 1H-MRS can be used to reveal reduced neuronal viability or function in the hippocampus and dorsolateral prefrontal cortex and altered membrane phospholipid metabolism in the dorsolateral prefrontal cortex in patients with depressive disorder. The 1H-MRS findings partially reflect the severity of the depressive disorder.     

双相障碍Ⅱ型患者前额叶白质、豆状核磁共振波谱分析

目的 探讨双相障碍Ⅱ型患者前额叶白质、豆状核的氢质子磁共振波谱(1H-MRS)特征. 方法 以自2012年9月至2013年4月在中山大学附属第三医院住院的双相障碍Ⅱ型患者30例为患者组,同期20例健康志愿者为对照组,采用多体素磁共振波谱技术检测2组研究对象前额叶白质、豆状核的代谢物质含量,包括N-乙酰天门冬氨酸(NAA)、胆碱化合物(Cho)、肌酸(Cr)、肌醇(mI),并计算NAA/Cr、Cho/Cr、mI/Cr、NAA/Cho、NAA/(Cho+Cr)的比值. 结果 患者组右侧前额叶白质NAA、Cho、mI绝对含量及NAA/Cr比值和对照组相比明显下降,差异均有统计学意义(P＜0.05);左侧前额叶白质NAA绝对含量及NAA/Cr、NAA/Cho、NAA/(Cho+Cr)比值与对照组相比明显下降,差异均有统计学意义(P＜0.05);右侧豆状核NAA、Cho绝对含量和对照组相比明显下降,差异有统计学意义(P＜0.05). 结论 双相障碍Ⅱ型患者存在双侧前额叶白质纤维受损和神经胶质细胞功能异常,以及右侧豆状核神经元缺失或功能异常.     

A subsequent-memory effect in dorsolateral prefrontal cortex

The importance of brain regions for long-term memory encoding has been examined by comparison of encoding-related neural activity on trials in which successful recollection subsequently occurred to the encoding-related activity on trials in which successful recollection did not occur. We applied similar analyses to event-related functional magnetic resonance imaging (fMRI) data to explore the relative roles of dorsolateral and ventrolateral prefrontal cortex (PFC) regions during specific components of a working-memory (WM) maintenance task. The results of this study indicated that increases in dorsolateral PFC activity during encoding was related to subsequent retrieval-success. These results lend support to the hypothesis that ventrolateral PFC mediates a limited-capacity WM buffer that supports rehearsal maintenance functions while dorsolateral PFC mediates WM organization functions that accommodate the capacity limits of WM maintenance.     

Effects of slow rTMS at the right dorsolateral prefrontal cortex on EEG asymmetry and mood

In a sham-controlled design (n = 12), slow repetitive transcranial magnetic stimulation (rTMS) was applied to the right dorsolateral prefrontal cortex for 20 min, and the subsequent effects on mood and the EEG spectrum were investigated, Analysis revealed a significant left hemisphere increase in EEG theta activity at 25-35 and 55-65 min after stimulation. In addition, participants reported significant decrease in anxiety immediately after stimulation, as well as 35 and 65 min after rTMS. These findings indicate that reductions in anxiety after slow rTMS at the right dorsolateral prefrontal cortex are associated with a contralateral increase in theta activity.     

The dorsolateral prefrontal cortex in idiom interpretation: an rTMS study

Neuropsychological studies have suggested that a prefrontal lesion can impair idiom comprehension. We tested the role of the dorsolateral prefrontal cortex (DLPFC) in idiom processing by using repetitive transcranial magnetic stimulation (rTMS) in normal participants. Each subject was presented with a written (idiomatic or literal) sentence followed by four pictures. rTMS was applied over left or right DLPFC or in a sham condition after picture presentation. Reaction times (RTs) decreased for the two types of sentence during rTMS, but accuracy was affected only in the case of idioms. The results show that both left and right DLPFC are involved in monitoring the idiomatic response, thus complementing neuropsychological studies.     

Left and right High Frequency repetitive Transcranial Magnetic Stimulation of the dorsolateral prefrontal cortex does not affect mood in female volunteers.

OBJECTIVE: High Frequency repetitive Transcranial Magnetic Stimulation (HF-rTMS) has yielded divergent results concerning its effect on mood in normal volunteers. In a former study, we were unable to demonstrate negative mood effects after one session of HF-rTMS on the left dorsolateral prefrontal cortex (DLPFC) in a large group of healthy female volunteers: researchers had focused mainly on negative mood changes, overlooking a possible positive mood induction, while no studies had yet examined mood effects of HF-rTMS delivered on the right prefrontal cortex. In this study, we have tried to replicate our previous HF-rTMS findings on the left DLPFC in a new (large) group of healthy female subjects, and we focused especially on positive mood changes. We also extended our former research by stimulating the right DLPFC in a different but comparable (large) group of healthy female volunteers with the same HF-rTMS parameters. METHODS: In this sham-controlled, single blind, crossover HF-rTMS study, stimulus parameters were an exact copy of our previous healthy volunteer study. To exclude individual anatomical differences, the left and right DLPFC were targeted under magnetic resonance (MRI) guidance. To examine subjective mood changes we used Visual Analogue Scales (VAS), the Profile of Mood States (POMS), and the Positive Affect and Negative Affect Schedule (PANAS), the latter to assure assessment of positive emotions. To detect any delayed mood changes, assessments were also re-administered 30min post-HF-rTMS. RESULTS: We were unable to demonstrate immediate or delayed mood changes after one single active HF-rTMS session on the left or right DLPFC. CONCLUSIONS: Although we took into account several methodological problems which might have confounded previous rTMS mood induction studies, the hypothesis that one single session of HF-rTMS on the left or on the right DLPFC can influence mood in healthy female volunteers was not supported. SIGNIFICANCE: One HF-rTMS session has no effect on subjective mood in healthy female volunteers.     

Metabolic alterations in the dorsolateral prefrontal cortex after treatment with high-frequency repetitive transcranial magnetic stimulation in patients with unipolar major depression

Neuroimaging studies suggest a specific role of anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC) in major depression. Stimulation of the latter by means of repetitive transcranial magnetic stimulation (rTMS) as an antidepressant intervention has increasingly been investigated in the past. The objective of the present study was to examine in vivo neurochemical alterations in both brain regions in 17 patients with unipolar major depression before and after 10 days of high-frequency (20Hz) rTMS of the left DLPFC using 3-tesla proton magnetic resonance spectroscopy. Six out of seventeen patients were treatment responders, defined as a 50% reduction of the Hamilton depression rating scale. No neurochemical alterations in the ACC were detected after rTMS. As compared to the non-responders, responders had lower baseline concentrations of DLPFC glutamate which increased after successful rTMS. Correspondingly, besides a correlation between clinical improvement and an increase in glutamate concentration, an interaction between glutamate concentration changes and stimulation intensity was observed. Our results indicate that metabolic, state-dependent changes within the left DLPFC in major depressive disorder involve the glutamate system and can be reversed in a dose-dependent manner by rTMS.     

Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia

Genetic linkage and association have implicated neuregulin-1 (NRG-1) as a schizophrenia susceptibility gene. We measured mRNA expression levels of the three major isoforms of NRG-1 (ie type I, type II, and type III) in the postmortem dorsolateral prefrontal cortex (DLPFC) from matched patients and controls using real-time quantitative RT-PCR. Expression levels of three internal controls-GAPDH, cyclophilin, and beta-actin-were unchanged in schizophrenia, and there were no changes in the absolute levels of the NRG-1 isoforms. However, type I expression normalized by GAPDH levels was significantly increased in schizophrenia DLPFC (by 23%) and positively correlated with antipsychotic medication dosage. Type II/type I and type II/type III ratios were significantly decreased (18 and 23% respectively). There was no effect on the NRG-1 mRNA levels of genotype at two SNPs previously associated with schizophrenia, suggesting that these alleles are not functionally responsible for abnormal NRG-1 expression patterns in patients. Subtle abnormalities in the expression patterns of NRG-1 mRNA isoforms in DLPFC may be associated with schizophrenia.     

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex and cortical excitability in patients with major depressive disorder

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex is a relatively non-invasive technique with putative therapeutic effects in major depression. However, the exact neurophysiological basis of these effects needs further clarification. Therefore, we studied the impact of ten daily sessions of left, dorsolateral prefrontal rTMS on motor cortical excitability, as revealed by transcranial magnetic stimulation-elicited motor-evoked potentials in 30 patients. As compared to the non-responders, responders (33%) showed changes in parameters pointing towards a reduced cortical excitability. These results suggest that repetitive transcranial magnetic stimulation of the dorsolateral, prefrontal cortex may have inhibitory effects on motor cortical neuronal excitability in patients with major depressive disorder. Furthermore, measurement of motor cortical excitability may be a useful tool for investigating and monitoring inhibitory brain effects of antidepressant stimulation techniques like rTMS.     

Reduced NAA levels in the dorsolateral prefrontal cortex of young bipolar patients

OBJECTIVE: Converging evidence implicates prefrontal circuits in the pathophysiology of bipolar disorder. Proton spectroscopy studies performed in adult bipolar patients assessing prefrontal regions have suggested decreased levels of N-acetylaspartate (NAA), a putative marker of neuronal integrity. In order to examine whether such abnormalities would also be found in younger patients, a 1H spectroscopy study was conducted that focused on the dorsolateral prefrontal cortex of children and adolescents with bipolar disorder. METHOD: The authors examined the levels of NAA, creatine plus phosphocreatine, and choline-containing molecules in the left dorsolateral prefrontal cortex of 14 bipolar disorder patients (mean age=15.5 years, SD=3, eight female) and 18 healthy comparison subjects (mean age=17.3, SD=3.7, seven female) using short echo time, single-voxel in vivo 1H spectroscopy. Absolute metabolite levels were determined using the water signal as an internal reference. RESULTS: Bipolar patients presented significantly lower NAA levels and a significant inverse correlation between choline-containing molecules and number of previous affective episodes. No differences were found for other metabolites. CONCLUSIONS: These findings suggest that young bipolar patients have decreased NAA levels in the dorsolateral prefrontal cortex, similar to what was previously reported in adult patients. Such changes may reflect an underdevelopment of dendritic arborizations and synaptic connections. These neuronal abnormalities in the dorsolateral prefrontal cortex of bipolar disorder youth are unlikely to represent long-term degenerative processes, at least in the subgroup of patients where the illness had relatively early onset.