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Effects of Creatine Monohydrate Augmentation on Brain Metabolic and Network Outcome Measures in Women With Major Depressive Disorder
Abstract
Background:
Creatine monohydrate (creatine) augmentation has the potential to accelerate the clinical responses to and enhance the overall efficacy of selective serotonin reuptake inhibitor treatment in women with major depressive disorder (MDD). Although it has been suggested that creatine augmentation may involve the restoration of brain energy metabolism, the mechanisms underlying its antidepressant efficacy are unknown.
Methods:
In a randomized, double-blind, placebo-controlled trial, 52 women with MDD were assigned to receive either creatine augmentation or placebo augmentation of escitalopram; 34 subjects participated in multimodal neuroimaging assessments at baseline and week 8. Age-matched healthy women (n = 39) were also assessed twice at the same intervals. Metabolic and network outcomes were measured for changes in prefrontal N-acetylaspartate and changes in rich club hub connections of the structural brain network using proton magnetic resonance spectroscopy and diffusion tensor imaging, respectively.
Results:
We found MDD-related metabolic and network dysfunction at baseline. Improvement in depressive symptoms was greater in patients receiving creatine augmentation relative to placebo augmentation. After 8 weeks of treatment, prefrontal N-acetylaspartate levels increased significantly in the creatine augmentation group compared with the placebo augmentation group. Increment in rich club hub connections was also greater in the creatine augmentation group than in the placebo augmentation group.
Conclusions:
N-acetylaspartate levels and rich club connections increased after creatine augmentation of selective serotonin reuptake inhibitor treatment. Effects of creatine administration on brain energy metabolism and network organization may partly underlie its efficacy in treating women with MDD.
... Since the brain is particularly susceptible to oxidative stress due to the high rates of oxygen consumption, increased mitochondrial oxidative stress and abnormalities in bioenergetics may induce structural and functional alterations of the brain [9,12,14]. Evidence also indicates that oxidative stress is one of the main causes of the structural and functional brain alterations that were reported in individuals with MDD: reduced volumes of the frontal cortex and the hippocampus [15,16,17]; decreased network connectivity of the brain [18]; and decreased metabolite levels in the specific brain regions [12,18,19,20,21,22]. ...
... Since the brain is particularly susceptible to oxidative stress due to the high rates of oxygen consumption, increased mitochondrial oxidative stress and abnormalities in bioenergetics may induce structural and functional alterations of the brain [9,12,14]. Evidence also indicates that oxidative stress is one of the main causes of the structural and functional brain alterations that were reported in individuals with MDD: reduced volumes of the frontal cortex and the hippocampus [15,16,17]; decreased network connectivity of the brain [18]; and decreased metabolite levels in the specific brain regions [12,18,19,20,21,22]. ...
... Preclinical study results also support an association between depression and increased oxidative stress in the brain [23,24,25] Energy metabolism of the human brain can be estimated using neuroimaging techniques such as 31 P-magnetic resonance spectroscopy ( 31 P-MRS) that measures the products of high energy phosphate metabolism, such as inorganic phosphate, nucleoside triphosphates (NTP), and phosphocreatine. Regional and/or global abnormalities in energy metabolism were reported in MDD [18,19,20,21,22]. Previous studies using 31 P-MRS showed that individuals with MDD had lower levels of NTP in the basal ganglia and frontal lobe, where structural alterations were also detected [19,20,21]. ...
Hypoxia inducible factor-1 (HIF-1) is a transcriptional factor that regulates gene expressions in response to decreased oxygen levels in the tissue, or hypoxia. HIF-1 exerts protective effects against hypoxia by mediating mitochondrial metabolism and consequently reducing oxidative stress. Recently, increased levels of oxidative stress and abnormal energy metabolism in the brain have been suggested to play essential roles in the pathogenesis of depression. Given that HIF-1 activates creatine metabolism and increases phosphocreatine levels in the intestinal epithelial cells, we assume that HIF-1 may induce similar processes in the brain. Elevated phosphocreatine levels in the brain, as measured by magnetic resonance spectroscopy, were associated with better treatment response to the antidepressants in individuals with depression. In addition, oral creatine supplements, which led to increased phosphocreatine levels in the brain, also enhanced the effects of antidepressants in individuals with depression. As such, we hypothesized that increasing the HIF-1, which potentially facilitates creatine metabolism in the brain, might be a new therapeutic target in depression. With this regard, we suggested that interventions to elevate the HIF-1 levels in the brain, including the intermittent hypoxia conditioning and hyperbaric oxygen therapy, might be considered as new additional treatments for depression.
... Furthermore, increasing evidence shows that energy metabolism is disturbed in depressive patients (15)(16)(17). Creatine, an important intermediate of energy metabolism, is widely involved in the recycling process of adenosine phosphate (ATP) (18)(19)(20). Importantly, creatinine is the metabolite of creatine, so we speculate that creatinine may be closely related to depression. ...
... In addition, Zhou et al. observed that creatine was downregulated in the plasma of children and adolescents with depression through metabolomics (43). While exogenous supplementation of creatine or ATP can alleviate depression (44, 45), the possible explanation is that creatine can accelerate the clinical response to selective serotonin reuptake inhibitors, promote the differentiation of neurons, and thus improve the overall efficacy (17,18,46). Therefore, creatine's effect on energy metabolism may be part of the basis for its treatment of depression. ...
Introduction
Previous studies have found that depressive patients tend to have low levels of creatinine; however, the extent to which creatinine levels are associated with depression has been poorly investigated. Therefore, this study aimed to explore the relationship between creatinine levels and depression.
Methods
The participants and follow-up data from the China Health and Retirement Longitudinal Study (CHARLS), as well as metabolomics data from the Metabolite Network of Depression Database (MENDA), were collected. The 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) was used to assess the severity of depression. Spearman correlation analysis, spline regression, and binary logistic regression models were employed to explore the relationship between creatinine levels and depression.
Results
A total of 7,826 participants and 3,886 follow-up participants were included in the CHARLS 2011 and 2015 surveys. Of these, 37.9% (2,966/7,826) and 34.6% (13,44/3,886) of participants experienced depression in CHARLS 2011 and 2015, respectively. The creatinine level was negatively correlated with the total CESD-10 score and dimensions scores, showing an inverse dose–response relationship between creatinine levels and depression. Compared with participants with high creatinine levels, those with middle creatinine levels were associated with a higher risk of depression (OR = 1.22, 95% CI = 1.08–1.38), while participants with low creatinine levels had the highest risk of depression (OR = 1.30, 95% CI = 1.13–1.49) in the fully adjusted model. Similar results were observed in the follow-up data, and the MENDA metabolomics data validated the negative correlation between creatinine levels and the severity of depression.
Conclusion
Lower levels of creatinine were closely associated with a higher risk of depression, and it could serve as a potential marker for identifying individuals at high risk of depression.
... Interestingly, the fronto-parietal regions along with the subcortical structures including the thalamus, putamen, and hippocampus are considered as highly inter-connected brain hubs, also referred to as "rich clubs" 5 . Connections between these rich clubs play a key role in promoting efficient information flow in the brain network, despite the high cost of white matter wiring [15][16][17] . Moreover, global efficiency of the brain network could be influenced by damages to the connections between rich clubs 15 . ...
... Network Construction. Detailed information on network construction is described elsewhere 17 . In brief, deterministic fiber tracking based on the Fiber Assignment by Continuous Tracking (FACT) algorithm was applied to reconstruct white matter tract 43 and fiber connectivity among the 82 ROIs was then calculated. ...
Brain network is organized to maximize the efficiency of both segregated and integrated information processing that may be related to human intelligence. However, there have been surprisingly few studies that focus on the topological characteristics of brain network underlying extremely high intelligence that is intellectual giftedness, particularly in adolescents. Here, we examined the network topology in 25 adolescents with superior intelligence (SI-Adol), 25 adolescents with average intelligence (AI-Adol), and 27 young adults with AI (AI-Adult). We found that SI-Adol had network topological properties of high global efficiency as well as high clustering with a low wiring cost, relative to AI-Adol. However, contrary to the suggested role that brain hub regions play in general intelligence, the network efficiency of rich club connection matrix, which represents connections among brain hubs, was low in SI-Adol in comparison to AI-Adol. Rather, a higher level of local connection density was observed in SI-Adol than in AI-Adol. The highly intelligent brain may not follow this efficient yet somewhat stereotypical process of information integration entirely. Taken together, our results suggest that a highly intelligent brain may communicate more extensively, while being less dependent on rich club communications during adolescence.
... Most recently using a similar patient cohort, it was shown that N-acetylaspartate levels and rich club connections increased after Cr augmentation of selective serotonin reuptake inhibitor treatment [92]. It was discussed that the antidepressive effects of creatine administration on brain energy metabolism and network organization may partly underlie its efficacy in treating women mit major depressive disorder [92]. ...
... Most recently using a similar patient cohort, it was shown that N-acetylaspartate levels and rich club connections increased after Cr augmentation of selective serotonin reuptake inhibitor treatment [92]. It was discussed that the antidepressive effects of creatine administration on brain energy metabolism and network organization may partly underlie its efficacy in treating women mit major depressive disorder [92]. These results suggest that Cr was indeed effective against depression. ...
The CK/PCr-system, with creatine (Cr) as an energy precursor, plays a crucial role in cellular physiology. In the kidney, as in other organs and cells with high and fluctuating energy requirements, energy-charged phospho-creatine (PCr) acts as an immediate high-energy source and energy buffer, and as an intracellular energy transport vehicle. A maximally filled total Cr (Cr plus PCr) pool is a prerequisite for optimal functioning of the body and its organs, and health. Skeletal- and cardiac muscles of dialysis patients with chronic kidney disease (CKD) are depleted of Cr in parallel with the duration of dialysis. The accompanying accumulation of cellular damage seen in CKD patients lead to a deterioration of musculo-skeletal and neurological functioning and poor quality of life (QOL). Therefore, to counteract Cr depletion, it is proposed to supplement CKD patients with Cr. The anticipated benefits include previously documented improvements in the musculo-skeletal system, brain and peripheral nervous system, as well as improvements in the common comorbidities of CKD patients (see below). Thus, with a relatively simple, safe and inexpensive Cr supplementation marked improvements in quality of life (QOL) and life span are likely reached. To avoid Cr and fluid overload by oral Cr administration, we propose intradialytic Cr supplementation, whereby a relatively small amount of Cr is added to the large volume of dialysis solution to a final concentration of 1-10mM. From there, Cr enters the patient’s circulation by back diffusion during dialysis. Because of the high affinity of the Cr transporter (CRT) for Cr affinity for Cr (Vmax of CRT for Cr = 20-40 μM Cr), Cr is actively transported from the blood stream into the target cells and organs, including skeletal and cardiac muscle, brain, proximal tubules of kidney epithelial cells, neurons, and leukocytes and erythrocytes, which all express CRT and depend on the CK/PCr system. By this intradialytic strategy, only as much Cr is taken up by the body as is needed to fill the tissue Cr pools and no excess Cr has to be excreted, as is the case with oral Cr. Because aqueous solutions of Cr are not very stable, Cr must be added immediately before dialysis either as solid Cr powder or from a frozen Cr stock solution to the dialysate, or alternatively, Cr could become an additional component of a novel dry dialysate mixture in a cartridge device.
... An earlier RCT had shown that creatine could improve cognitive measures in patients with unipolar and bipolar depression (Toniolo et al., 2017). Low levels of creatine in the prefrontal cortex have been associated with depressive symptomatology (Faulkner et al., 2021), thus restoring prefrontal creatine and related metabolites (Yoon et al., 2016) could be of importance for effective psychotherapy because this brain area is implicated in CBT functioning (Yuan et al., 2022). Whether similar benefits could be observed for other psychological treatments requires further research. ...
... Así lo expuso un estudio realizado en 52 mujeres con trastorno depresivo mayor tratadas con un inhibidor selectivo de la recaptación de serotonina. La suplementación con 5 g de monohidrato de Cr desde la segunda semana de tratamiento logró mejoras significativas en comparación con el placebo (Yoon, 2016y Bakian, 2020. ...
La creatina es el suplemento deportivo más popular por su contribución al rendimiento deportivo y al mejoramiento de la composición corporal. Debido a que cumple funciones no solo a nivel muscular, sino en todos los tejidos del cuerpo, especialmente en el sistema nervioso, su interés como ayuda en diversas condiciones de salud y enfermedad ha crecido en las últimas décadas. Sin embargo, muchas de las investigaciones han sido realizadas en animales, en modelos que no representan tan adecuadamente las realidades del ser humano, en quienes la creatina mejoraría características de la función cognitiva principalmente. En la presente revisión narrativa se detallan los hallazgos más importantes de investigaciones recientes efectuadas en seres humanos en la última década, tendientes a analizar el beneficio de la creatina en funciones cognitivas, depresión, daño al sistema nervioso central, enfermedades neurodegenerativas, salud cardiovascular y otras condiciones relevantes. Además, se discute el concepto de seguridad en su dosificación, incluyendo los resultados de estudios individuales, revisiones y metaanálisis recientes.
... The connectivity strength of rich-club connections in the precuneus was reduced in the subjective memory complaint individuals with depression compared with those without depression, which was correlated with the severity of depressive symptoms (Kim et al., 2019). After 8 weeks of pharmacological treatment, significantly enhanced rich club connections were observed in the patients (Yoon et al., 2016). However, other studies had not found significant differences in rich club connections between MDD and controls (He et al., 2022), and the discrimination before and after treatment was poor . ...
Introduction
It has been suggested that the rich club organization in major depressive disorder (MDD) was altered. However, it remained unclear whether the rich club organization could be served as a biomarker that predicted the improvement of clinical symptoms in MDD.
Methods
The current study included 29 mild or moderate patients with MDD, who were grouped into a treatment group (receiving cognitive behavioral therapy or real‐time fMRI feedback treatment) and a no‐treatment group. Resting‐state MRI scans were obtained for all participants. Graph theory was employed to investigate the treatment‐related changes in network properties and rich club organization.
Results
We found that patients in the treatment group had decreased depressive symptom scores and enhanced rich club connectivity following the nonpharmacological treatment. Moreover, the changes in rich club connectivity were significantly correlated with the changes in depressive symptom scores. In addition, the nonpharmacological treatment on patients with MDD increased functional connectivity mainly among the salience network, default mode network, frontoparietal network, and subcortical network. Patients in the no‐treatment group did not show significant changes in depressive symptom scores and rich club organization.
Conclusions
Those results suggested that the remission of depressive symptoms after nonpharmacological treatment in MDD patients was associated with the increased efficiency of global information processing.
... In addition, some published metabolomics results suggest that some metabolites related to energy metabolism are abnormal in the MDD brains, which reveals that MDD symptom is accompanied by abnormal energy consumption in the brain (Abdallah et al., 2014;Yoon et al., 2016;Zuccoli et al., 2017;MacDonald et al., 2019;Li et al., 2022). We have explored the correlation between neural energy and neural activity in a series of past studies (Zhu et al., 2019;Wang et al., 2021;Yuan et al., 2021), which provides a theoretical basis for our exploration of energy income and expenditure in MDD. ...
Major depressive disorder (MDD) is a serious psychiatric disorder, with an increasing incidence in recent years. The abnormal dopaminergic pathways of the midbrain cortical and limbic system are the key pathological regions of MDD, particularly the ventral tegmental area- nucleus accumbens- medial prefrontal cortex (VTA-NAc-mPFC) neural circuit. MDD usually occurs with the dysfunction of dopaminergic neurons in VTA, which decreases the dopamine concentration and metabolic rate in NAc/mPFC brain regions. However, it has not been fully explained how abnormal dopamine concentration levels affect this neural circuit dynamically through the modulations of ion channels and synaptic activities. We used Hodgkin-Huxley and dynamical receptor binding model to establish this network, which can quantitatively explain neural activity patterns observed in MDD with different dopamine concentrations by changing the kinetics of some ion channels. The simulation replicated some important pathological patterns of MDD at the level of neurons and circuits with low dopamine concentration, such as the decreased action potential frequency in pyramidal neurons of mPFC with significantly reduced burst firing frequency. The calculation results also revealed that NaP and KS channels of mPFC pyramidal neurons played key roles in the functional regulation of this neural circuit. In addition, we analyzed the synaptic currents and local field potentials to explain the mechanism of MDD from the perspective of dysfunction of excitation-inhibition balance, especially the disinhibition effect in the network. The significance of this article is that we built the first computational model to illuminate the effect of dopamine concentrations for the NAc-mPFC-VTA circuit between MDD and normal groups, which can be used to quantitatively explain the results of existing physiological experiments, predict the results for unperformed experiments and screen possible drug targets.
... An animal model suggests sex-dependent differences in the effect of creatine supplementation, assuming an improvement in depressive behavior in females [272]. Consistent with this finding, the clinical study conducted on a group of women of different ages suggested that this protein improves the effects of antidepressant drugs, increases the connection of neural networks, which are attenuated in people with these conditions, and increases levels of N-acetyl aspartate in the prefrontal cortex, indicative of the improvement in neuronal integrity [273]. Likewise, dopaminergic and serotonergic neurotransmitters are increased with the presence of creatine detected in the cerebrospinal fluid [274]. ...
Major depressive disorder (MDD) is an incapacitating condition characterized by loss of interest, anhedonia and low mood, which affects almost 4% of people worldwide. With rising prevalence, it is considered a public health issue that affects economic productivity and heavily increases health costs alone or as a comorbidity for other pandemic non-communicable diseases (such as obesity, cardiovascular disease, diabetes, inflammatory bowel diseases, etc.). What is even more noteworthy is the double number of women suffering from MDD compared to men. In fact, this sex-related ratio has been contemplated since men and women have different sexual hormone oscillations, where women meet significant changes depending on the age range and moment of life (menstruation, premenstruation, pregnancy, postpartum, menopause…), which seem to be associated with susceptibility to depressive symptoms. For instance, a decreased estrogen level promotes decreased activation of serotonin transporters. Nevertheless, sexual hormones are not the only triggers that alter neurotransmission of monoamines and other neuropeptides. Actually, different dietary habits and/or nutritional requirements for specific moments of life severely affect MDD pathophysiology in women. In this context, the present review aims to descriptively collect information regarding the role of malnutrition in MDD onset and course, focusing on female patient and especially macro- and micronutrient deficiencies (amino acids, ω3 polyunsaturated fatty acids (ω3 PUFAs), folate, vitamin B12, vitamin D, minerals…), besides providing evidence for future nutritional intervention programs with a sex-gender perspective that hopefully improves mental health and quality of life in women.
... comparisons with no asterisk had a P[0.05 and were considered not significant]. disorders [14,18,34,35]. Notably, several studies have demonstrated that ATP plays an essential role in astrocytemodulated depressive-like behaviors [14,18]. ...
Food deprivation can rescue obesity and overweight-induced mood disorders, and promote mood performance in normal subjects. Animal studies and clinical research have revealed the antidepressant-like effect of calorie restriction, but little is known about the mechanism of calorie restriction-induced mood modification. Previous studies have found that astrocytes modulate depressive-like behaviors. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant isoform in mediating astrocyte Ca2+ signals and its genetic knockout mice are widely used to study astrocyte function in vivo. In this study, we showed that deletion of IP3R2 blocked the antidepressant-like effect induced by calorie restriction. In vivo microdialysis experiments demonstrated that calorie restriction induced an increase in ATP level in the medial prefrontal cortex (mPFC) in naïve mice but this effect disappeared in IP3R2-knockout mice, suggesting a role of astrocytic ATP in the calorie restriction-induced antidepressant effect. Further experiments showed that systemic administration and local infusion of ATP into the mPFC induced an antidepressant effect, whereas decreasing ATP by Apyrase in the mPFC blocked calorie restriction-induced antidepressant regulation. Together, these findings support a role for astrocytic ATP in the antidepressant–like effect caused by calorie restriction.
... Reports since the early 1980s have suggested that creatine metabolism and/or availability may have antidepressive effects [312][313][314][315][316][317][318]. These studies and others have provided the basis for assessing the effects of creatine and/or creatine precursors like S-adenosyl-Lmethionine (SAMe) and GAA affect brain phosphagen levels, markers of depression, and/or the therapeutic efficacy of antidepressant medications [8,169,170]. ...
Although creatine has been mostly studied as an ergogenic aid for exercise, training, and sport, several health and potential therapeutic benefits have been reported. This is because creatine plays a critical role in cellular metabolism, particularly during metabolically stressed states, and limitations in the ability to transport and/or store creatine can impair metabolism. Moreover, increasing availability of creatine in tissue may enhance cellular metabolism and thereby lessen the severity of injury and/or disease conditions, particularly when oxygen availability is compromised. This systematic review assesses the peer-reviewed scientific and medical evidence related to creatine’s role in promoting general health as we age and how creatine supplementation has been used as a nutritional strategy to help individuals recover from injury and/or manage chronic disease. Additionally, it provides reasonable conclusions about the role of creatine on health and disease based on current scientific evidence. Based on this analysis, it can be concluded that creatine supplementation has several health and therapeutic benefits throughout the lifespan.
... Moreover, abnormal cerebral metabolism associated with depression was shown more common in women [6]. Yoon et al. reported that NAA level in prefrontal cortex was negatively associated with depression symptom in females with MDD [7]. In addition, emerging multimodal neuroimaging studies showed that abnormal brain energy metabolism was associated with the topological characteristic of the brain, which influenced the efficiency of network communication in MDD patients [8]. ...
Despite the high incidence of major depressive disorder (MDD) in females, the detailed neurobiology mechanism remains not fully understood. Increasing evidence showed that MDD was associated with hippocampal volumetric abnormality with different subfields demonstrating various alteration features. However, the linkage between hippocampal atrophy with its biochemical information remains unclear. In this study, we aim to investigate the relationship between bilateral hippocampal subfields volumetric and metabolic information in female MDD patients, using a combined T1-weighted magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1 H-MRS) technology. There are 15 female MDD patients and 12 matched healthy controls involved in the study. We found a significant decrease in left fimbria volume in MDD group, which was negatively correlated with left hippocampal choline level. In addition, the left hippocampal creatine concentration in patients was negatively correlated with left fimbria volume. Moreover, the NAA level in left hippocampus was negatively correlated with MDD clinical symptomology including anxiety and depression scores. Our findings suggest that the altered coupling between hippocampal structural and metabolic features might contribute to the etiology of female MDD patients.
... Additionally, higher connectivity strength of rich-club connections is associated with positive changes in general functioning over time in schizophrenia [89,90]. Rich-club connections among rich-club nodes are lower in major depressive disorder (MDD) and late-life depression patients than in healthy controls, in which higher rich-club connectivity is associated with lower symptom severity score (i.e., Hamilton Depression Rating Scale) [91,92]. However, the remission of MDD patients is more strongly associated with feederlocal subnetworks than with rich-club connections [93], suggesting that compensatory effects from treatment may be more distinct in non-core brain regions in patients with this psychiatric disorder. ...
The brain is a complex network. Growing evidence supports the critical roles of a set of brain regions within the brain network, known as the brain’s cores or hubs. These regions require high energy cost but possess highly efficient neural information transfer in the brain’s network and are termed the rich-club. The rich-club of the brain network is essential as it directly regulates functional integration across multiple segregated regions and helps to optimize cognitive processes. Here, we review the recent advances in rich-club organization to address the fundamental roles of the rich-club in the brain and discuss how these core brain regions affect brain development and disorders. We describe the concepts of the rich-club behind network construction in the brain using graph theoretical analysis. We also highlight novel insights based on animal studies related to the rich-club and illustrate how human studies using neuroimaging techniques for brain development and psychiatric/neurological disorders may be relevant to the rich-club phenomenon in the brain network.
... Each structural connection (edge) between two NOIs was defined as having a minimum of 3 http://surfer.nmr.mgh.harvard.edu three interconnected streamlines, which were measured using the deterministic fiber tracking method (Yoon et al., 2016). For each individual, a 17 × 17 structural connection matrix was constructed per hemisphere. ...
The propensity to engage in risky behaviors including excessive alcohol consumption may impose increased medical, emotional, and psychosocial burdens. Personality and behavioral traits of individuals may contribute in part to the involvement in risky behaviors, and therefore the classification of one’s traits may help identify those who are at risk for future onset of the addictive disorder and related behavioral issues such as alcohol misuse. Personality and behavioral characteristics including impulsivity, anger, reward sensitivity, and avoidance were assessed in a large sample of healthy young adults (n = 475). Participants also underwent diffusion tensor imaging for the analysis of structural brain networks. A data-driven clustering using personality and behavioral traits of the participants identified four subtypes. As compared with individuals clustered into the neutral type, individuals with a high level of impulsivity (A subtype) and those with high levels of reward sensitivity, impulsivity, anger, and avoidance (B subtype) showed significant associations with problem drinking. In contrast, individuals with high levels of impulsivity, anger, and avoidance but not reward sensitivity (C subtype) showed a pattern of social drinking that was similar to those of the neutral subtype. Furthermore, logistic regression analysis with ridge estimators was applied to demonstrate the neurobiological relevance for the identified subtypes according to distinct patterns of structural brain connectivity within the addiction circuitry [neutral vs. A subtype, the area under the receiver operator characteristic curve (AUC) = 0.74, 95% CI = 0.67–0.81; neutral vs. B subtype, AUC = 0.74, 95% CI = 0.66–0.82; neutral vs. C subtype, AUC = 0.77, 95% CI = 0.70–0.84]. The current findings enable the characterization of individuals according to subtypes based on personality and behavioral traits that are also corroborated by neuroimaging data and may provide a platform to better predict individual risks for addictive disorders.
... This latter finding is particularly significant because the creation of network connections between so-called "rich-club hubs" is particularly expensive from the energetic point of view, 132,133 thus it makes sense that creatine pretreatment may improve it, as it actually did in the research we just reported. 131 Kious et al 134 In a dose-finding study on 18 patients (14 women) affected by major depression creatine was administered at 3 g/d for 1 week followed by 5 g/d for 3 more weeks or at 5 g/d for 1 week followed by 10 g/d for 3 more weeks. ...
Creatine is pivotal in energy metabolism of muscle and brain cells, both in physiological and in pathological conditions. Additionally, creatine facilitates the differentiation of muscle and neuronal cells. Evidence of effectiveness of creatine supplementation in improving several clinical conditions is now substantial, and we review it in this paper. In hereditary diseases where its synthesis is impaired, creatine has a disease‐modifying capacity, especially when started soon after birth. Strong evidence, including a Cochrane meta‐analysis, shows that it improves muscular strength and general well‐being in muscular dystrophies. Significant evidence exists also of its effectiveness in secondary prevention of statin myopathy and of treatment‐resistant depression in women. Vegetarians and vegans do not consume any dietary creatine and must synthesize all they need, spending most of their methylation capacity. Nevertheless, they have a lower muscular concentration of creatine. Creatine supplementation has proved effective in increasing muscular and neuropsychological performance in vegetarians or vegans and should, therefore, be recommended especially in those of them who are athletes, heavy‐duty laborers or who undergo intense mental effort. Convincing evidence also exists of creatine effectiveness in muscular atrophy and sarcopenia in the elderly, and in brain energy shortage (mental fatigue, sleep deprivation, environmental hypoxia as in mountain climbing, and advanced age). Furthermore, we review more randomized, placebo‐controlled trials showing that creatine supplementation is safe up to 20 g/d, with a possible caveat only in people with kidney disease. We trust that the evidence we review will be translated into clinical practice and will spur more research on these subjects.
... Clinically, no serious side effects have been reported for the IV administration of 1-2 g of PCr daily for the treatment of the above-mentioned diseases [31]. Besides, clinical studies have reported the safety of 3-5 g/day of orally administered creatine for MDD [32][33][34]. Our animal studies found that intraperitoneal injection of 125 mg/kg PCr in depressed rats producing the best efficacy; thus, IV administration of PCr at 1 g (125 mg/kg × 0.08 × 60 kg) twice daily was chosen in this study [35]. ...
Background
Major depressive disorder (MDD) is a common psychiatric disorder. With systematic antidepressant treatment, 50–75% of patients have a treatment response but require 4–6 weeks to have their symptoms alleviated. Therefore, researchers anticipate the development of novel fast-acting antidepressants. Previous studies have revealed that the decrease of bio-energetic metabolism may contribute to the occurrence of depression, while our team has found adenosine triphosphate (ATP) and phosphocreatine (PCr) to be fast-acting antidepressants in the depressed-animal model. ATP and PCr have already been widely prescribed clinically as energy supplements for cells. This will be the first clinical attempt of the intravenous administration of ATP and PCr combined with orally administered fluoxetine in MDD.
Methods
This is a single-center, randomized, double-blind, placebo-controlled pilot study. A total of 42 patients will be divided randomly into three groups. Patients will receive an intravenous administration of ATP or PCr or saline twice daily combined with orally administered fluoxetine (20 mg/day) for the first 2 weeks and fluoxetine monotherapy for the following 4 weeks. Follow-up assessment will be completed at week 10. Feasibility outcomes will include percentages of patient eligibility, intention to use medication, willingness to participate, drug adherence, completion of the scheduled assessment, retention, drop-out, etc. Physical examination results, Side Effect Rating Scale, adverse events, results from blood tests, electroencephalogram, and electrocardiograph will be recorded for safety evaluation of the augmentation therapy. The trends of efficacy will be evaluated by the reduction rate of the Hamilton Depression Rating Scale, the mean change of the Clinical Global Impression Scale, and the Patients Health Questionaire-9 items.
Discussion
In our study, ATP and PCr will be given by intravenous infusion. Thus patients will be hospitalized for the initial 2 weeks for safety concern. Hospitalization will be an impact factor for the recruitment, participation, drop-out, efficacy, results, etc. The evaluation of our feasibility outcomes, study setting, safety of augmentation therapy and possible efficacy trends among groups, will facilitate a full-scale trial design and sample size calculation.
Trial registration
NCT03138681. Registered on 3 May 2017. First patient: 4 May 2017.
Electronic supplementary material
The online version of this article (10.1186/s13063-018-3115-4) contains supplementary material, which is available to authorized users.
... For instance, an MRS study found that a positive response to thyroid hormone (T3) augmentation of SSRI treatment in patients who were resistant to stand-alone SSRI therapy was associated with changes in levels of phosphocreatine and total nucleoside triphosphate (primarily representing ATP) (Iosifescu et al., 2008;Lyoo et al., 2012). Recently, creatine (compared to placebo) administration as an add-on treatment to escitalopram in women with MDD has been reported to lead to increased levels of prefrontal Nacetylaspartate (NAA; a marker of neuronal viability and integrity) and to the improvement of connectivity, which are otherwise reduced in MDD, between high-degree hubs of the brain (Yoon et al., 2016). A series of preclinical studies by the same research group reported that dopaminergic, adrenergic and serotonergic systems are all implicated in the antidepressive effects of creatine (Cunha et al., 2012(Cunha et al., , 2013aCunha et al., 2013b). ...
Given the moderate efficacy of the currently available antidepressants (ADs) in the treatment of major depressive disorder (MDD), the identification of agents that are both able to enhance the effectiveness of ADs and have a good safety profile is a reasonable task for current psychopharmacology. In addition to the well-known drugs (second-generation antipsychotics, levothyroxine, dopaminergic agents, etc.) for augmentation, investigations suggest that several nutraceuticals and over-the-counter (OTC) drugs may be effective and safe as adjunct therapeutic agents to conventional ADs. To identify such active ingredients we first performed a systematic literature search using PubMed and then conducted both backward and forward citation searches. For the PubMed search, we used the following combinations of keywords: 1) “adjunctive” + “therapy” + “antidepressant”; 2) “add-on” + “therapy” + “antidepressant”; 3) “supplementation” + “therapy” + “antidepressant”. As a result of those efforts, we found more than 20 agents (e.g. S-Adenosyl-L-Methionine; folate; ω-3 fatty acids; curcumin; N-acetylcysteine; saffron; 5-hydroxytryptophan; NSAIDs) that are supposedly effective in the augmentation of standard AD treatment. We discussed the possible mechanisms of the antidepressant actions of those agents, as well as the preclinical and clinical evidence for their efficacy as stand-alone and adjunct treatments for MDD.
... Lyoo et al. (2012) showed an improvement in depressive symptoms in a group of 52 women with depression that received creatine combined with escitalopram for 8 weeks, as early as week 2 of treatment, maintained at weeks 4 and 8 as compared to the placebo group (Lyoo et al., 2012). These findings were later extended by showing neuroimaging results from the same patients, demonstrating an increase on Nacetylaspartate levels and rich club connections after creatine augmentation therapy, suggesting that creatine can improve brain energy metabolism (Yoon et al., 2015). In another study, 14 females with depression and comorbid methamphetamine dependence enrolled in an 8week open label trial of daily creatine treatment presented significant reduction in Hamilton Depression Rating Scale scores as early as week 2 when compared to baseline scores (Hellem et al., 2015). ...
Depression, a highly prevalent neuropsychiatric disorder worldwide, causes a heavy burden for the society and is associated with suicide risk. The treatment of this disorder remains a challenge, since currently available antidepressants provide a slow and, often, incomplete response and cause several side effects that contribute to diminish the adhesion of patients to treatment. In this context, several nutraceuticals have been investigated regarding their possible beneficial effects for the management of this neuropsychiatric disorder. Creatine stands out as a supplement frequently used for ergogenic purpose, but it also is a neuroprotective compound with potential to treat or mitigate a broad range of central nervous systems diseases, including depression. This review presents preclinical and clinical evidence that creatine may exhibit antidepressant properties. The focus is given on the possible molecular mechanisms underlying its effects based on the results obtained with different animal models of depression. Finally, evidence obtained in animal models of depression addressing the possibility that creatine may produce rapid antidepressant effect, similar to ketamine, are also presented and discussed.
... Recent studies have shown that the nutraceutical compound creatine produces a promising antidepressant effect in animal models (Allen, 2012;Allen et al., 2010, Cunha et al., 2012, 2013a, 2013b, 2014a, 2015a, 2015b, 2017, 2017 and clinical trials (Kondo et al., 2011(Kondo et al., , 2016Lyoo et al., 2012;Roitman et al., 2007;Yoon et al., 2016), suggesting that creatine supplementation may be a novel approach for the treatment of MDD. Although the mechanisms underlying the antidepressant effect of creatine remain not fully elucidated, the monoamine and adenosine receptors activation, NMDA receptor inhibition, and the activation of several intracellular kinases have been implicated in its effect (Cunha et al., 2012(Cunha et al., , 2013a(Cunha et al., , 2013b(Cunha et al., , 2014a(Cunha et al., , 2015a(Cunha et al., , 2015b. ...
Creatine has been shown to play a significant role in the pathophysiology and treatment of major depressive disorder (MDD) in preclinical and clinical studies. However, the biological mechanisms underlying its antidepressant effect is still not fully elucidated. This study investigated the effect of creatine (p.o.) administered for 21 days in the behavior of mice submitted to tail suspension test (TST), a predictive test of antidepressant activity. Creatine reduced the immobility time in the TST (1–10 mg/kg), without affecting locomotor activity, a finding consistent with an antidepressant profile. Creatine administration increased the ubiquitous creatine kinase (uCK) and creatine kinase brain isoform (CK-B) mRNA in the hippocampus of mice. Taking into account that PGC-1α induces FNDC5/irisin expression mediating BDNF-dependent neuroplasticity, the effect of creatine administration (1 mg/kg, p. o.) on the hippocampal PGC-1α, FNDC5 and BDNF gene expression was investigated. Creatine treatment increased PGC-1α, FNDC5 and BDNF mRNA in the hippocampus as well as BDNF immunocontent. The involvement of BDNF downstream intracellular signaling pathway mediated by Akt, proapoptotic proteins BAX and BAD and antiapoptotic proteins Bcl2 and Bcl-xL was also investigated following creatine treatment. Creatine increased Akt (Ser 473) phosphorylation, and Bcl2 mRNA and protein levels, and Bcl-xL mRNA, whereas BAD mRNA was decreased following creatine administration in the hippocampus. Altogether these results indicate that creatine antidepressant-like effect may be dependent on Akt activation and increased expression of the neuroprotective proteins in the hippocampus of mice. The obtained data reinforce the antidepressant property of creatine and highlight the role of these molecular targets in the pathophysiology of MDD.
... 157 In this study, Cr response was associated with normalization of the brain's rich club hub network connections and increases in prefrontal NAA concentrations. 158 Reductions in brain PCr levels are also more pronounced in female methamphetamine users, who are more likely to exhibit depression than male counterparts. 159 Supplementation with Cr, even in the absence of an antidepressant, improves brain PCr levels and depression scores in women with depression and methamphetamine dependence. ...
Learning objectives:
After participating in this activity, learners should be better able to:• Assess epidemiologic evidence that increased altitude of residence is linked to increased risk of depression and suicide• Evaluate strategies to address hypoxia-related depression and suicidal ideation ABSTRACT: Suicide and major depressive disorder (MDD) are complex conditions that almost certainly arise from the influences of many interrelated factors. There are significant regional variations in the rates of MDD and suicide in the United States, suggesting that sociodemographic and environmental conditions contribute. Here, we review epidemiological evidence that increases in the altitude of residence are linked to the increased risk of depression and suicide. We consider the possibility that chronic hypobaric hypoxia (low blood oxygen related to low atmospheric pressure) contributes to suicide and depression, which is suggested by animal models, short-term studies in humans, and the effects of hypoxic medical conditions on suicide and depression. We argue that hypobaric hypoxia could promote suicide and depression by altering serotonin metabolism and brain bioenergetics; both of these pathways are implicated in depression, and both are affected by hypoxia. Finally, we briefly examine treatment strategies to address hypoxia-related depression and suicidal ideation that are suggested by these findings, including creatine monohydrate and the serotonin precursors tryptophan and 5-hydroxytryptophan.
... In fact, a double-blind placebocontrolled trial that included fifty-two female subjects with unipolar depression showed that supplementation with creatine monohydrate (5 g daily) for 8 weeks as an augmentation of treatment with escitalopram was safe and effective (Lyoo et al. 2012). A subsample of 34 patients that were enrolled in this trial also participated in multimodal neuroimaging assessments and those who had received creatine supplementation had levels of N-acetyl aspartate (NAA) increased in the prefrontal cortex and rich club connections enriched as evidenced through proton magnetic resonance spectroscopy ( 1 H-MRS) and diffusion tensor imaging (DTI), respectively (Yoon et al. 2016). ...
Depressive episodes are a major cause of morbidity and dysfunction in individuals suffering from bipolar disorder. Currently available treatments for this condition have limited efficacy and new therapeutic options are needed. Extensive research in the pathophysiology of bipolar disorder points to the existence of mitochondrial and bioenergetic dysfunction. We hypothesized that creatine monohydrate, a nutraceutical that works as a mitochondrial modulator, would be effective as an adjunctive therapy for bipolar depression. We conducted a double-blind trial in which 35 patients with bipolar disorder type I or II in a depressive episode by DSM-IV criteria and in use of regular medication for the treatment of this phase of the disease were randomly allocated into two adjunctive treatment groups for 6 weeks: creatine monohydrate 6 g daily (N = 17) or placebo (N = 18). Primary efficacy was assessed by the change in the Montgomery–Åsberg Depression Rating Scale (MADRS). We did not find a statistically significant difference in the comparison between groups for the change in score on the MADRS after 6 weeks in an intention-to-treat (ITT) analysis (p = 0.560; Cohen’s d = 0.231). However, we found significant superiority of creatine add-on vs. placebo when we considered the remission criterion of a MADRS score ≤ 12 at week 6 analyzing the outcome of the 35 randomized patients on ITT (52.9% remission in the creatine group vs. 11.1% remission in the placebo group) and of the 23 completers (66.7% remission in the creatine group vs. 18.2% remission in the placebo group) (p = 0.012; OR = 9.0 and p = 0.036; OR = 9.0, respectively). Two patients who received creatine switched to hypomania/mania early in the trial. No clinically relevant physical side-effects were reported or observed. This proof-of-concept study, aiming to restore brain bioenergetics using an adjunctive mitochondrial modulator, is not conclusive on the efficacy of creatine add-on for bipolar depression, but suggests that this compound may have a role in the adjunctive treatment of this phase of the illness. Further investigation through randomized controlled trials with larger samples should be conducted to verify the efficacy of creatine supplementation for bipolar depression and also for subsyndromal depressive symptoms.
... Neuropsychiatric disorders and their responses to clinical treatments are typically associated with changes in cognitive processing, which are usually accompanied by alterations in both structural and functional brain networks. On the structural side, for example, patients with Alzheimer's disease (AD) and major depressive disorder (MDD) exhibit gray matter loss in regions of the DMN and FPN (Bozzali et al. 2006;Frodl et al. 2008;He et al. 2008;Seeley et al. 2009;van Tol et al. 2010;Schmaal et al. 2017); patients with MDD and Parkinson's disease (PD) manifest structural restorations in regions of the FPN, DMN and SMN after exposure to drug treatment and stimulated intervention (van Hartevelt et al. 2014;Yoon et al. 2016;Qin et al. 2017). Intriguingly, Crossley et al. (2014) performed a meta-analysis of structural MRI data in 26 brain disorders and showed that gray matter atrophy in most disorders is mainly located in the regions of the DMN, FPN, and SMN that are evident in brain hubs. ...
Neuropsychiatric disorders are increasingly conceptualized as disconnection syndromes that are associated with abnormal network integrity in the brain. However, whether different neuropsychiatric disorders show commonly dysfunctional connectivity architectures in large-scale brain networks remains largely unknown. Here, we performed a meta-connectomic study to identify disorder-related functional modules and brain regions by combining meta-analyses of 182 published resting-state functional MRI studies in 11 neuropsychiatric disorders and graph-theoretical analyses of 3 independent resting-state functional MRI datasets with healthy and diseased populations (Alzheimer's disease and major depressive disorder [MDD]). Three major functional modules, the default mode, frontoparietal, and sensorimotor networks were commonly abnormal across disorders. Moreover, most of the disorders preferred to target the network connector nodes that were primarily involved in intermodule communications and multiple cognitive components. Apart from these common dysfunctions, different brain disorders were associated with specific alterations in network modules and connector regions. Finally, these meta-connectomic findings were confirmed by two empirical example cases of Alzheimer's disease and MDD. Collectively, our findings shed light on the shared biological mechanisms of network dysfunctions of diverse disorders and have implications for clinical diagnosis and treatment from a network perspective.
... Indeed, strategies that increase the brain energy supply have been shown to improve depressive symptoms in individuals with MDD. For example, application of creatine monohydrate, which targets brain energy metabolism, significantly improves depressive symptoms in animal models (Allen, D'Anci, Kanarek, & Renshaw, 2010) and in patients suffering from MDD (Lyoo et al., 2012;Yoon et al., 2015). Not surprisingly, impaired mitochondrial bioenergetic function has been hypothesized to contribute to the pathophysiology of MDD. ...
Depression is a chronic, recurring, and serious mood disorder that afflicts up to 20% of the global population. The monoamine hypothesis has dominated our understanding of the pharmacotherapy of depression for more than half a century; however, our understanding of the pathophysiology and pathogenesis of major depression has lagged far behind. Astrocytes are the most abundant and versatile cells in the brain, participating in most, if not all, of brain functions as both a passive housekeeper and an active player. Mounting evidence from clinical, preclinical and post-mortem studies has revealed a decrease in the number or density of astrocytes and morphological and functional astroglial atrophy in patients with major depressive disorder (MDD) and in animal models of depression. Furthermore, currently available antidepressant treatments at least partially exert their therapeutic effects on astrocytes. More importantly, dysfunctional astrocytes lead to depressive-like phenotypes in animals. Together, current studies point to astroglial pathology as the potential root cause of MDD. Thus, a shift from a neuron-centric to an astrocyte-centric cause of MDD has gained increasing attention during the past two decades. Here we will summarize the current evidence supporting the hypothesis that MDD is a disease of astrocyte pathology and highlight previous studies on promising strategies that directly target astrocytes for the development of novel antidepressant treatments.
... [33][34][35] One study reported that the increment in rich club hub connections was greater in the creatine group than in the placebo group, suggesting the effects of creatine administration on brain network organization may partly underlie its efficacy in treating women with MDD. 36 Moreover, compared with patients who had current MDD, those with remitted MDD showed an altered pattern of intracommunicability within the default mode network (DMN) and intercommunicability between the DMN and other subnetworks, including the visual recognition network and salience network, after treatment with selective serotonin reuptake inhibitors. 37 However, FA reductions in these involved regions (e.g., superior frontal, superior parietal and precentral areas and precuneus) were found in patients with MDD versus controls in some original studies. ...
Background:
Multiple meta-analyses of diffusion tensor imaging (DTI) studies have reported impaired white matter integrity in patients with major depressive disorder (MDD). However, owing to inclusion of medicated patients in these studies, it is difficult to conclude whether these reported alterations are associated with MDD or confounded by medication effects. A meta-analysis of DTI studies on medication-free (medication-naive and medication washout) patients with MDD would therefore be necessary to disentangle MDD-specific effects.
Methods:
We analyzed white matter alterations between medication-free patients with MDD and healthy controls using anisotropic effect size-signed differential mapping (AES-SDM). We used DTI query software for fibre tracking.
Results:
Both pooled and subgroup meta-analyses in medication washout patients showed robust fractional anisotropy (FA) reductions in white matter of the right cerebellum hemispheric lobule, body of the corpus callosum (CC) and bilateral superior longitudinal fasciculus III (SLF III), whereas FA reductions in the genu of the CC and right anterior thalamic projections were seen in only medication-naive patients. Fibre tracking showed that the main tracts with observed FA reductions included the right cerebellar tracts, body of the CC, bilateral SLF III and arcuate fascicle.
Limitations:
The analytic techniques, patient characteristics and clinical variables of the included studies were heterogeneous; we could not exclude the effects of nondrug therapies owing to a lack of data.
Conclusion:
By excluding the confounding influences of current medication status, findings from the present study may provide a better understanding of the underlying neuropathology of MDD.
... Several studies have demonstrated bioenergetics abnormalities in MDD, providing several evidences of energetic impairment and severe metabolic mitochondrial dysfunction in MDD. Moreover, studies have observed impaired mitochondrial metabolic function, increased levels of lactate, and changes in cerebral metabolic rate in MDD [18][19][20][21]. In addition, these alterations may affect brain energy metabolism, as well as result in reductions of the length and complexity of dendritic arbors of several neuronal populations [22]. ...
The aim of this study is to assess Neuron-Specific Enolase (NSE) levels and clinical features in subjects with major depressive disorder (MDD). This is a cross-sectional study with drug-naïve young adults with MDD (aged 18-29 years). Serum levels of NSE were assessed using the electrochemiluminescence method. MDD diagnosis, suicidal ideation, and time of disease were assessed using the Structured Clinical Interview for DSM-IV (SCID). The Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) were used to assess depressive and anxiety symptoms. No relationship was observed between NSE levels and severity of depressive and anxiety symptoms, time of disease, and suicidal ideation. These results suggest that NSE serum levels were not associated with clinical features of MDD among drug-naïve young adults.
Background and objectives
Alzheimer’s disease (AD) is more prevalent in women than in men; however, there is a discrepancy in research on sex differences in AD. The human brain is a large-scale network with hub regions forming a central core, the rich-club, which is vital to cognitive functions. However, it is unknown whether alterations in the rich-clubs in AD differ between men and women. We aimed to investigate sex differences in the rich-club organization in the brains of patients with AD.
Methods
In total, 260 cognitively unimpaired individuals with negative amyloid positron emission tomography (PET) scans, 281 with prodromal AD (mild cognitive impairment due to AD) and 285 with AD dementia who confirmed with positive amyloid PET scans participated in the study. We obtained high-resolution T1-weighted and diffusion tensor images and performed network analysis.
Results
We observed sex differences in the rich-club and feeder connections in patients with AD, suggesting lower structural connectivity strength in women than in men. We observed a significant group-by-sex interaction in the feeder connections, particularly in the thalamus. In addition, the connectivity strength of the thalamus in the feeder connections was significantly correlated with general cognitive function in only men with prodromal AD and women with AD dementia.
Conclusion
Our findings provide important evidence for sex-specific alterations in the structural brain network related to AD.
Background:
Numerous magnetic resonance spectroscopy (MRS) studies have reported metabolic abnormalities in the brains of patients with depression, although inconsistent results have been reported. The aim of this study was to explore changes in neurometabolite levels in patients with depression across large-scale MRS studies.
Method:
A total of 307 differential metabolite entries associated with depression were retrieved from 180 MRS studies retrieved from the Metabolite Network of Depression Database. The vote-counting method was used to identify consistently altered metabolites in the whole brain and specific brain regions of patients with depression.
Results:
Only few differential neurometabolites showed a stable change trend. The levels of total choline (tCho) and the tCho/N-acetyl aspartate (NAA) ratio were consistently higher in the brains of patients with depression, and that the levels of NAA, glutamate and glutamine (Glx), and gamma-aminobutyric acid (GABA) were lower. For specific brain regions, we found lower Glx levels in the prefrontal cortex and lower GABA concentrations in the occipital cortex. We also found lower concentrations of NAA in the anterior cingulate cortex and prefrontal cortex. The levels of tCho were higher in the prefrontal cortex and putamen.
Conclusion:
Our results revealed that most altered neurometabolites in previous studies lack of adequate reproducibility. Through vote-counting method with large-scale studies, downregulation of glutamatergic neurometabolites, impaired neuronal integrity, and disturbed membrane metabolism were found in the pathobiology of depression, which contribute to existing knowledge of neurometabolic changes in depression. Further studies based on a larger dataset are needed to confirm our findings.
Disrupted rich-club organization has been extensively studied in major depressive disorder (MDD) patients. Although data indicate that neuroplasticity-based computerized cognitive remediation (nCCR) can accelerate clinical responses in MDD patients, the mechanisms underlying its antidepressant efficacy are unknown. In this study, all MDD patients underwent two (baseline and week 4) neuropsychological assessments and DTI imaging. Additionally, 17 MDD patients did nCCR for 30 hours spread across 4 weeks. Rich-club organization was calculated with a graph-theoretical approach, and SC-FC coupling was explored. After 4 weeks of treatment, the number of rich-club connections, global efficiency, and SC-FC coupling strength increased significantly and were negatively associated with TMT-B scores. The effects of nCCR on disrupted rich-club organization may partly underlie its efficacy in improving the executive function of patients with MDD. Effects of nCCR on disrupted rich-club organization may partly underlie its efficacy in improving the executive function of patients with MDD.
Background
Stressful life events (SLEs) are well-established proximal predictors of the onset of depression. However, the fundamental causes of interindividual differences in depression outcomes are poorly understood. This study addressed this depression susceptibility mechanism using a well-powered sample of adults living in China.
Methods
Healthy participants with SLEs (n = 185; mean = 47.51 years, 49.73% female), drawn from a longitudinal study on the development of depression, underwent diffusion tensor imaging, interleukin-6 (IL-6) level measurement, and trimonthly standardized clinical and scale evaluations within a two-year period.
Results
Receiver operating characteristic analyses indicated that reduced feeder connection and HIP.R nodal efficiency improved the predictive accuracy of post-SLEs depression (ORfeeder = 0.623, AUC = 0.869, P < 0.001; ORHIP = 0.459, AUC = 0.855, P < 0.001). The successfully established path analysis model confirmed the significant partial effect of SLEs-IL-6-white matter (WM) network differences-depression (onset and severity) (x²/8 = 1.453, goodness-of-fit [GFI] = 0.935, standard root-mean-square error of approximation [SRMR] = 0.024). Females, individuals with lower exercise frequency (EF) or annual household income (AHI) were more likely to have higher IL-6 level after SLEs (βint-female⁎SLEs = −0.420, P < 0.001; βint-exercise⁎SLEs = −0.412, P < 0.001; βint-income⁎SLEs = −0.302, P = 0.005).
Limitations
The sample size was restricted due to the limited incidence rate and prospective follow-up design.
Conclusions
Our results suggested that among healthy adults after SLEs, those who exhibited abnormal IL-6-WM differences were susceptible to developing depression. Females, lower AHI or EF might account for an increased risk of developing these abnormal IL-6-WM differences.
El monohidrato de creatina es uno de los suplementos más estudiados en el mundo de la nutrición deportiva por su rol energético e hipertrófico en el músculo esquelético. En la actualidad, se puede estar subestimando el amplio espectro de beneficios terapéuticos que aporta a la salud en otra población que pueda requerir de sus ventajas, como el sector clínico, más allá de solo relacionarlo con la mejora en las adaptaciones al ejercicio físico. En esta revisión narrativa se tiene como objetivo abordar la interacción de la suplementación con creatina y la salud del cerebro humano, conforme a la investigación disponible que hasta la fecha se ha publicado en humanos; principalmente, los efectos de la ingesta regular en la función cognitiva, las enfermedades neurodegenerativas y los trastornos psiquiátricos. La evidencia científica apoya firmemente los beneficios de la suplementación con creatina en personas que presentan los llamados errores innatos del metabolismo, como el síndrome de deficiencia de creatina causado por alteraciones genéticas en GAMT y AGAT. Además, en la función cognitiva, la suplementación con creatina podría ofrecer mayores beneficios en sujetos estresados o adultos mayores. También brindaría un efecto adicional ante los trastornos relacionados con la depresión y los síntomas de depresión unipolar y bipolar, si se combina con la medicación antidepresiva. En estas cuestiones anteriormente mencionadas, la literatura se encuentra en cierta forma mejor dilucidada en comparación con los presuntos beneficios en enfermedades neurodegenerativas, como las enfermedades de Parkinson y Huntington, y por el momento menos respaldada en el caso de la enfermedad de Alzheimer. Se requiere una mayor cantidad de investigaciones realizadas a mayor escala y con mejores diseños de estudio en humanos, con el fin de elaborar mejores protocolos de suplementación en poblaciones que presentan distintas condiciones de salud. Palabras clave: creatina, cerebro, depresión, trastornos
Major depressive disorder (MDD) is a serious psychiatric disorder that associated with high rate of disability and increasing suicide rate, and the pathogenesis is still unclear. Many researches showed that the energy metabolism of patients with depression is impaired, which may be the direction of depression treatment. In this review, we focus on the "omics" technologies such as genomics, proteomics, transcriptomics and metabolomics, as well as imaging, and the progress on energy metabolism of MDD. These findings indicate that abnormal energy metabolism is one of the important mechanisms for the occurrence and development of depression. Although the research on various mechanisms of depression is still ongoing, the rapid development of new technologies and the joint use of various technologies will help to clarify the pathogenesis of depression and explore efficient diagnosis and treatment methods.
Mood disorders such as depression and bipolar disorder are common mental illnesses, affecting millions of patients worldwide. The application of newly available brain imaging methods to the study of mood disorders holds substantial promise in uncovering the brain mechanisms affected in these illnesses. This comprehensive and authoritative text features contributions from leading international experts, providing easily accessible information on the study of the brain mechanisms involved in the causation of mood disorders and the available treatments. Topics covered include the potential of magnetoencephalography (MEG), neuroimaging brain inflammation in depression, electrophysiology studies in mood disorders, and the applications of machine learning, filling an important gap in available neuropsychiatric literature and highlighting new developments. An invaluable resource for practitioners in the fields of psychiatry, neurology, primary care medicine, and related mental health professions, as well as researchers, students, graduate and post-graduate trainees.
Introduction:
Neuroglial functions may be deteriorated in major depressive disorder (MDD).
Objective:
To evaluate the markers of glial and neuronal cell turnover and to explore their associations with brain metabolites.
Methods:
In 10 participants with MDD and 10 healthy controls (HC) we investigated neuronal and glial plasma markers (the neuron-specific enolase, NSE; and S100beta, S100B) and brain metabolites (N-acetyl aspartate, NAA; total choline, Cho; and total creatine, Cr). Blood was collected for NSE and S100B. NAA, Cho, and Cr metabolite levels were measured in the anterior cingulate cortex (ACC) with proton magnetic resonance spectroscopy (1H-MRS) at 3T.
Results:
NSE and S100B levels were significantly higher in MDD subjects than in HC. The Cr level was significantly higher in MDD subjects than in HC, but the NAA and Cho levels did not differ between groups. NAA/Cr and Cho/Cr ratios were significantly lower in patients with MDD versus HC. S100B was negatively correlated with the Cho levels.
Conclusions:
These results provide supporting evidence of neuronal and glial distress in MDD. Neuronal viability appears decreased, whereas glial regenerative activity and energy metabolism in the ACC increase in acute major depressive episode. Since low concentrations of S100B have neuroplastic effects, these changes may indicate a possible compensatory mechanism.
The association between subjective memory complaints (SMCs) and depressive symptoms has been widely reported and both have been regarded as risk factors for dementia, such as Alzheimer’s disease (AD). Although SMCs arise as early as in middle age, the exact neural correlates of comorbid depressive symptoms among individuals who are middle-aged and with SMCs have not yet been well investigated. Because rich-club organization of the brain plays a key role in the pathophysiology of various neuropsychiatric disorders, the investigation of rich club organization may provide insight regarding the neurobiological mechanisms of depressive symptoms in SMCs. In the current study, we compared the rich-club organization in the structural brain connectivity between individuals who have SMCs along with depressive symptoms (SMCD) and individuals with SMCs but without depressive symptoms (SMCO). A total of 53 individuals with SMCD and 91 individuals with SMCO participated in the study. For all participants, high-resolution, T1-weighted images and diffusion tensor images were obtained, and the network analysis was performed. Individuals with SMCD had lower connectivity strength between the precuneus and other rich-club nodes than those with SMCO, which was significant after adjusting for potential confounders. Our findings suggest that disruptions of rich-club connectivity strength of the precuenus are associated with depressive symptoms in middle-aged individuals with SMCs. Given that the precuneus is one of the commonly affected regions in the early stages of AD, our findings may imply that the concomitant depressive symptoms in middle-aged individuals with SMCs could reflect structural alterations related to AD.
Despite the high incidence of major depressive disorder (MDD) in females, the detailed neurobiology mechanism remains not fully understood. Increasing evidence showed that MDD was associated with hippocampal volumetric abnormality with different subfields demonstrating various alteration features. However, the linkage between hippocampal atrophy with its biochemical information remains unclear. In this study, we aim to investigate the relationship between bilateral hippocampal subfields volumetric and metabolic information in female MDD patients, using a combined T1weighted magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (H-MRS) technology. There are 15 female MDD patients and 12 matched healthy controls involved in the study. We found a significant decrease in left fimbria volume in MDD group, which was negatively correlated with left hippocampal choline level. In addition, the left hippocampal creatine concentration in patients was negatively correlated with left fimbria volume. Moreover, the NAA level in left hippocampus was negatively correlated with MDD clinical symptomology including anxiety and depression scores. Our findings suggest that the altered coupling between hippocampal structural and metabolic features might contribute to the etiology of female MDD patients.
Objective:
Depression among methamphetamine users is more prevalent in females than males, but gender specific treatment options for this comorbidity have not been described. Reduced brain phosphocreatine levels have been shown to be lower in female methamphetamine users compared to males, and, of relevance, studies have demonstrated an association between treatment resistant depression and reduced brain phosphocreatine concentrations. The nutritional supplement creatine monohydrate has been reported to reduce symptoms of depression in female adolescents and adults taking antidepressants, as well as to increase brain phosphocreatine in healthy volunteers. Therefore, the purpose of this pilot study was to investigate creatine monohydrate as a treatment for depression in female methamphetamine users.
Methods:
Fourteen females with depression and comorbid methamphetamine dependence were enrolled in an 8-week open label trial of 5 grams of daily creatine monohydrate and of these 14, eleven females completed the study. Depression was measured using the Hamilton Depression Rating Scale (HAMD) and brain phosphocreatine levels were measured using phosphorus magnetic resonance spectroscopy pre- and post-creatine treatment. Secondary outcome measures included anxiety symptoms, measured with the Beck Anxiety Inventory (BAI), as well as methamphetamine use, monitored by twice weekly urine drug screens and self-reported use.
Results:
The results of a linear mixed effects repeated measures model showed significantly reduced HAMD and BAI scores as early as week 2 when compared to baseline scores. This improvement was maintained through study completion. Brain phosphocreatine concentrations were higher at the second phosphorus magnetic resonance spectroscopy scan compared to the baseline scan; Mbaseline = 0.223 (SD = 0.013) vs. Mpost-treatment = 0.233 (SD = 0.009), t(9) = 2.905, p < .01, suggesting that creatine increased phosphocreatine levels. Also, a reduction in methamphetamine positive urine drug screens of greater than 50% was observed by week 6. Finally, creatine was well tolerated and adverse events that were related to gastrointestinal symptoms and muscle cramping were determined as possibly related to creatine.
Conclusions:
The current study suggests that creatine treatment may be a promising therapeutic approach for females with depression and comorbid methamphetamine dependence. This study is registered on clinicaltrials.gov (NCT01514630).
Major depressive disorder (MDD) has been linked to imbalanced communication among large-scale brain networks, as reflected by abnormal resting-state functional connectivity (rsFC). However, given variable methods and results across studies, identifying consistent patterns of network dysfunction in MDD has been elusive.
To investigate network dysfunction in MDD through a meta-analysis of rsFC studies.
Seed-based voxelwise rsFC studies comparing individuals with MDD with healthy controls (published before June 30, 2014) were retrieved from electronic databases (PubMed, Web of Science, and EMBASE) and authors contacted for additional data.
Twenty-seven seed-based voxel-wise rsFC data sets from 25 publications (556 individuals with MDD and 518 healthy controls) were included in the meta-analysis.
Coordinates of seed regions of interest and between-group effects were extracted. Seeds were categorized into seed-networks by their location within a priori functional networks. Multilevel kernel density analysis of between-group effects identified brain systems in which MDD was associated with hyperconnectivity (increased positive or reduced negative connectivity) or hypoconnectivity (increased negative or reduced positive connectivity) with each seed-network.
Major depressive disorder was characterized by hypoconnectivity within the frontoparietal network, a set of regions involved in cognitive control of attention and emotion regulation, and hypoconnectivity between frontoparietal systems and parietal regions of the dorsal attention network involved in attending to the external environment. Major depressive disorder was also associated with hyperconnectivity within the default network, a network believed to support internally oriented and self-referential thought, and hyperconnectivity between frontoparietal control systems and regions of the default network. Finally, the MDD groups exhibited hypoconnectivity between neural systems involved in processing emotion or salience and midline cortical regions that may mediate top-down regulation of such functions.
Reduced connectivity within frontoparietal control systems and imbalanced connectivity between control systems and networks involved in internal or external attention may reflect depressive biases toward internal thoughts at the cost of engaging with the external world. Meanwhile, altered connectivity between neural systems involved in cognitive control and those that support salience or emotion processing may relate to deficits regulating mood. These findings provide an empirical foundation for a neurocognitive model in which network dysfunction underlies core cognitive and affective abnormalities in depression.
Low field nuclear magnetic resonance (NMR) was used to study the effect of different contents and types of resistant starch (RS) on dough quality. Inverse recovery (IR) sequence was used to acquire the sample’s NMR relaxation data during dough proofing. Firmness and stickiness were measured by a Texture Analyzer. An increasing trend of firmness and stickiness was observed as the content of resistant starch was increased in the dough. Data showed the appropriate RS content of adding was 5%(g/g). From magnetic resonance image (MRI), the moisture migration and distribution were quite uniform after 1~2h proofing during proofing process. This study showed the advantage of NMR technology, and this method could be used for the development of dough-based products containing RS in food industry.
Because of the wide availability of hardware as well as of standardized analytic quantification tools, proton magnetic resonance spectroscopy (¹H-MRS) has become widely used to study psychiatric disorders. ¹H-MRS allows measurement of brain concentrations of more traditional singlet neurometabolites like N-acetylaspartate, choline, and creatine. More recently, quantification of the more complex multiplet spectra for glutamate, glutamine, inositol, and γ-aminobutyric acid have also been implemented. Here we review applications of ¹H-MRS in terms of informing treatment options in schizophrenia, bipolar disorder, and major depressive disorders. We first discuss recent meta-analytic studies reporting the most reliable findings. Then we evaluate the more sparse literature focused on 1H-MRS-detected neurometabolic effects of various treatment approaches in psychiatric populations. Finally we speculate on future developments that may result in translation of these tools to improve the treatment of psychiatric disorders.
Importance:
The human brain forms a large-scale structural network of regions and interregional pathways. Recent studies have reported the existence of a selective set of highly central and interconnected hub regions that may play a crucial role in the brain's integrative processes, together forming a central backbone for global brain communication. Abnormal brain connectivity may have a key role in the pathophysiology of schizophrenia.
Objective:
To examine the structure of the rich club in schizophrenia and its role in global functional brain dynamics.
Design:
Structural diffusion tensor imaging and resting-state functional magnetic resonance imaging were performed in patients with schizophrenia and matched healthy controls.
Setting:
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.
Participants:
Forty-eight patients and 45 healthy controls participated in the study. An independent replication data set of 41 patients and 51 healthy controls was included to replicate and validate significant findings. MAIN OUTCOME(S) AND MEASURES: Measures of rich club organization, connectivity density of rich club connections and connections linking peripheral regions to brain hubs, measures of global brain network efficiency, and measures of coupling between brain structure and functional dynamics.
Results:
Rich club organization between high-degree hub nodes was significantly affected in patients, together with a reduced density of rich club connections predominantly comprising the white matter pathways that link the midline frontal, parietal, and insular hub regions. This reduction in rich club density was found to be associated with lower levels of global communication capacity, a relationship that was absent for other white matter pathways. In addition, patients had an increase in the strength of structural connectivity-functional connectivity coupling.
Conclusions:
Our findings provide novel biological evidence that schizophrenia is characterized by a selective disruption of brain connectivity among central hub regions of the brain, potentially leading to reduced communication capacity and altered functional brain dynamics.
Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a Gq G protein-coupled receptor only in astrocytes to enable selective activation of astrocytic Ca(2+) signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.
Recent findings have demonstrated that a small set of highly connected brain regions may play a central role in enabling efficient
communication between cortical regions, together forming a densely interconnected “rich club.” However, the density and spatial
layout of the rich club also suggest that it constitutes a costly feature of brain architecture. Here, combining anatomical
T1, diffusion tensor imaging, magnetic transfer imaging, and functional MRI, several aspects of structural and functional connectivity
of the brain's rich club were examined. Our findings suggest that rich club regions and rich club connections exhibit high
levels of wiring volume, high levels of white matter organization, high levels of metabolic energy usage, long maturational
trajectories, more variable regional time series, and more inter-regional functional couplings. Taken together, these structural
and functional measures extend the notion that rich club organization represents a high-cost feature of brain architecture
that puts a significant strain on brain resources. The high cost of the rich club may, however, be offset by significant functional
benefits that the rich club confers to the brain network as a whole.
Many anxiety disorders, as well as major depressive disorder (MDD), are at least twice as prevalent in women as in men, but the neurobiological basis of this discrepancy has not been well studied. MDD is often precipitated by exposure to uncontrollable stress, and is frequently characterized by abnormal or disrupted prefrontal cortex (PFC) function. In animals, exposure to stress has been shown to cause PFC dysfunction, but sex differences in this effect have not been investigated. The present study tested male and female rats on a PFC-dependent working memory task after administration of FG7142, a benzodiazepine inverse agonist that activates stress systems in the brain. Female rats were impaired by lower doses than males during proestrus (high estrogen), but not during estrus (low estrogen). Similarly, ovariectomized females showed increased stress sensitivity only after estrogen replacement. These results suggest that estrogen amplifies the stress response in PFC, which may increase susceptibility to stress-related disorders.
Objective:
Antidepressants targeting monoaminergic neurotransmitter systems, despite their immediate effects at the synaptic level, usually require several weeks of administration to achieve clinical efficacy. The authors propose a strategy of adding creatine monohydrate (creatine) to a selective serotonin reuptake inhibitor (SSRI) in the treatment of patients with major depressive disorder. Such augmentation may lead to a more rapid onset of antidepressant effects and a greater treatment response, potentially by restoring brain bioenergetics at the cellular level.
Method:
Fifty-two women with major depressive disorder were enrolled in an 8-week double-blind placebo-controlled clinical trial and randomly assigned to receive escitalopram in addition to either creatine (5 g/day, N=25) or placebo (N=27). Efficacy was primarily assessed by changes in the Hamilton Depression Rating Scale (HAM-D) score.
Results:
In comparison to the placebo augmentation group, patients receiving creatine augmentation showed significantly greater improvements in HAM-D score, as early as week 2 of treatment. This differential improvement favoring creatine was maintained at weeks 4 and 8. There were no differences between treatment groups in the proportion of patients who discontinued treatment prematurely (creatine: N=8, 32.0%; placebo: N=5, 18.5%) or in the overall frequency of all reported adverse events (creatine: 36 events; placebo: 45 events).
Conclusions:
The current study suggests that creatine augmentation of SSRI treatment may be a promising therapeutic approach that exhibits more rapid and efficacious responses in women with major depressive disorder.
Network studies of human brain structural connectivity have identified a specific set of brain regions that are both highly connected and highly central. Recent analyses have shown that these putative hub regions are mutually and densely interconnected, forming a "rich club" within the human brain. Here we show that the set of pathways linking rich club regions forms a central high-cost, high-capacity backbone for global brain communication. Diffusion tensor imaging (DTI) data of two sets of 40 healthy subjects were used to map structural brain networks. The contributions to network cost and communication capacity of global cortico-cortical connections were assessed through measures of their topology and spatial embedding. Rich club connections were found to be more costly than predicted by their density alone and accounted for 40% of the total communication cost. Furthermore, 69% of all minimally short paths between node pairs were found to travel through the rich club and a large proportion of these communication paths consisted of ordered sequences of edges ("path motifs") that first fed into, then traversed, and finally exited the rich club, while passing through nodes of increasing and then decreasing degree. The prevalence of short paths that follow such ordered degree sequences suggests that neural communication might take advantage of strategies for dynamic routing of information between brain regions, with an important role for a highly central rich club. Taken together, our results show that rich club connections make an important contribution to interregional signal traffic, forming a central high-cost, high-capacity backbone for global brain communication.
Background:
Many studies using diffusion tensor imaging (DTI) have demonstrated impaired white matter integrity in patients with major depressive disorder (MDD), with significant results found in diverse brain regions. We sought to identify whether there are consistent changes of regional white matter integrity in patients with MDD, as shown by decreased fractional anisotropy in DTI.
Method:
A systematic search strategy was used to identify relevant whole brain voxel-based DTI studies of patients with MDD in relation to comparison groups. Relevant databases were searched for studies published between January 1994 and February 2011 using combinations of the terms "DTI" or "diffusion tensor;" "whole brain" or "voxel-based;" and "depress*." Using the studies that met our inclusion criteria, we performed a meta-analysis of the coordinates of decreased fractional anisotropy using the activation likelihood estimation (ALE) method, which detects 3-dimensional conjunctions of coordinates from multiple studies, weighted by sample size. We then used DTIquery software for fibre tracking to locate the fascicles involved in each region.
Results:
We included 11 studies with a combined sample of 231 patients with MDD and 261 comparison participants, providing 50 coordinates of decreased fractional anisotropy. Our meta-analysis identified 4 consistent locations of decreased fractional anisotropy in patients with MDD: white matter in the right frontal lobe, right fusiform gyrus, left frontal lobe and right occipital lobe. Fibre tracking showed that the main fascicles involved were the right inferior longitudinal fasciculus, right inferior fronto-occipital fasciculus, right posterior thalamic radiation and interhemispheric fibres running through the genu and body of the corpus callosum.
Limitations:
The number of studies included was relatively small, and the DTI data acquisition and analysis techniques were heterogeneous. The ALE method cannot handle studies with no significant group differences.
Conclusion:
Voxel-based analysis of DTI studies of patients with MDD consistently identified decreased fractional anisotropy in the white matter fascicles connecting the prefrontal cortex within cortical (frontal, temporal and occipital lobes) and subcortical areas (amygdala and hippocampus). This isstrong evidence for the involvement of these neural circuits in the pathology of MDD.
A modification of the Bonferroni procedure for testing multiple hypotheses is presented. The method, based on the ordered p-values of the individual tests, is less conservative than the classical Bonferroni procedure but is still simple to apply. A simulation study shows that the probability of a type I error of the procedure does not exceed the nominal significance level, α, for a variety of multivariate normal and multivariate gamma test statistics. For independent tests the procedure has type I error probability equal to α. The method appears particularly advantageous over the classical Bonferroni procedure when several highly-correlated test statistics are involved.
The brain is expensive, incurring high material and metabolic costs for its size--relative to the size of the body--and many aspects of brain network organization can be mostly explained by a parsimonious drive to minimize these costs. However, brain networks or connectomes also have high topological efficiency, robustness, modularity and a 'rich club' of connector hubs. Many of these and other advantageous topological properties will probably entail a wiring-cost premium. We propose that brain organization is shaped by an economic trade-off between minimizing costs and allowing the emergence of adaptively valuable topological patterns of anatomical or functional connectivity between multiple neuronal populations. This process of negotiating, and re-negotiating, trade-offs between wiring cost and topological value continues over long (decades) and short (millisecond) timescales as brain networks evolve, grow and adapt to changing cognitive demands. An economical analysis of neuropsychiatric disorders highlights the vulnerability of the more costly elements of brain networks to pathological attack or abnormal development.
The human brain is a complex network of interlinked regions. Recent studies have demonstrated the existence of a number of highly connected and highly central neocortical hub regions, regions that play a key role in global information integration between different parts of the network. The potential functional importance of these "brain hubs" is underscored by recent studies showing that disturbances of their structural and functional connectivity profile are linked to neuropathology. This study aims to map out both the subcortical and neocortical hubs of the brain and examine their mutual relationship, particularly their structural linkages. Here, we demonstrate that brain hubs form a so-called "rich club," characterized by a tendency for high-degree nodes to be more densely connected among themselves than nodes of a lower degree, providing important information on the higher-level topology of the brain network. Whole-brain structural networks of 21 subjects were reconstructed using diffusion tensor imaging data. Examining the connectivity profile of these networks revealed a group of 12 strongly interconnected bihemispheric hub regions, comprising the precuneus, superior frontal and superior parietal cortex, as well as the subcortical hippocampus, putamen, and thalamus. Importantly, these hub regions were found to be more densely interconnected than would be expected based solely on their degree, together forming a rich club. We discuss the potential functional implications of the rich-club organization of the human connectome, particularly in light of its role in information integration and in conferring robustness to its structural core.
Increased rostral anterior cingulate cortex (rACC) activity has emerged as a promising predictor of treatment response in depression, but neither the reliability of this relationship nor the mechanisms supporting it have been thoroughly investigated. This review takes a three-pronged approach to these issues. First, I present a meta-analysis demonstrating that the relationship between resting rACC activity and treatment response is robust. Second, I propose that the rACC plays a key role in treatment outcome because of its 'hub' position in the default network. Specifically, I hypothesize that elevated resting rACC activity confers better treatment outcomes by fostering adaptive self-referential processing and by helping to recalibrate relationships between the default network and a 'task-positive network' that comprises dorsolateral prefrontal and dorsal cingulate regions implicated in cognitive control. Third, I support this hypothesis by reviewing neuropsychological, electrophysiological, and neuroimaging data on frontocingulate dysfunction in depression. The review ends with a discussion of the limitations of current work and future directions.
Brain imaging studies of major depressive disorder have shown alterations in the brain regions typically involved in episodic memory, including the prefrontal cortex and medial temporal areas. Some studies of major depressive disorder have linked episodic memory performance to treatment response. In this study, we sought to identify brain regions whose activity, measured during the encoding of pictures, predicted symptomatic improvement after 8 weeks of citalopram treatment.
We included 20 unmedicated depressed patients. These patients performed an episodic recognition memory task during functional magnetic resonance imaging. During the encoding phase, 150 pictures depicting emotionally positive, negative or neutral content were presented, and the participants were required to classify each picture according to its emotional valence. The same 150 pictures were presented, along with 150 new ones, for a recognition task. We asked participants to distinguish the old pictures from the new ones. We assessed symptom severity by use of the 21-item Hamilton Rating Scale for Depression (HAM-D) at baseline and after 8 weeks of citalopram treatment. We performed subsequent memory effect analyses using SPM2 software. We explored the relation between brain activation during successful encoding of pictures and symptomatic improvement.
Patients showed a mean symptomatic improvement of 54.5% on the HAM-D after 8 weeks. Symptomatic improvement was significantly and positively correlated with picture recognition memory accuracy. We also found that the activity of the ventromedial prefrontal cortex and anterior cingulate cortex during successful encoding was significantly correlated with symptomatic improvement. Finally, we found greater activation in the ventromedial prefrontal cortex during the successful encoding of positive pictures in comparison with neutral pictures.
During the recognition memory task, 5 participants (among the best responders to treatment) were not included in the valence-specific analyses because they had very few errors. A more challenging task would have allowed the inclusion of most patients.
Different types of functional imaging paradigms have been used to explore whether the activity of specific brain regions measured at baseline is predictive of a better response to treatment in major depressive disorder. Among these regions, the medial prefrontal cortex and anterior cingulate cortex usually show the strongest predictive value. According to our results, the medial prefrontal cortex and anterior cingulate cortex could have an effect on treatment response in major depressive disorder by contributing to the successful encoding of positively valenced information.
Impairments in bioenergetic function, cellular resiliency, and structural plasticity are associated with the pathogenesis of mood disorders. Preliminary evidence suggests that creatine, an ergogenic compound known to promote cell survival and influence the production and usage of energy in the brain, can improve mood in treatment-resistant patients. This study examined the effects of chronic creatine supplementation using the forced swim test (FST), an animal model selectively sensitive to antidepressants with clinical efficacy in human beings. Thirty male (experiment 1) and 36 female (experiment 2) Sprague-Dawley rats were maintained on either chow alone or chow blended with either 2% w/w creatine monohydrate or 4% w/w creatine monohydrate for 5 weeks before the FST. Open field exploration and wire suspension tests were used to rule out general psychostimulant effects. Male rats maintained on 4% creatine displayed increased immobility in the FST as compared with controls with no differences by diet in the open field test, whereas female rats maintained on 4% creatine displayed decreased immobility in the FST and less anxiety in the open field test compared with controls. Open field and wire suspension tests confirmed that creatine supplementation did not produce differences in physical ability or motor function. The present findings suggest that creatine supplementation alters depression-like behavior in the FST in a sex-dependent manner in rodents, with female rats displaying an antidepressant-like response. Although the mechanisms of action are unclear, sex differences in creatine metabolism and the hormonal milieu are likely involved.
Mitochondrial electron transport generates the ATP that is essential for the excitability and survival of neurons, and the protein phosphorylation reactions that mediate synaptic signaling and related long-term changes in neuronal structure and function. Mitochondria are highly dynamic organelles that divide, fuse, and move purposefully within axons and dendrites. Major functions of mitochondria in neurons include the regulation of Ca(2+) and redox signaling, developmental and synaptic plasticity, and the arbitration of cell survival and death. The importance of mitochondria in neurons is evident in the neurological phenotypes in rare diseases caused by mutations in mitochondrial genes. Mitochondria-mediated oxidative stress, perturbed Ca(2+) homeostasis, and apoptosis may also contribute to the pathogenesis of prominent neurological diseases including Alzheimer's, Parkinson's, and Huntington's diseases; stroke; amyotrophic lateral sclerosis; and psychiatric disorders. Advances in understanding the molecular and cell biology of mitochondria are leading to novel approaches for the prevention and treatment of neurological disorders.
The purpose of this study was to evaluate whether the concentration of beta-nucleoside triphosphate is lower in the basal ganglia of depressed subjects.
In vivo 31P magnetic resonance spectra were acquired from a 45-cm3 region surrounding the basal ganglia of 35 unmedicated depressed subjects and 18 comparison subjects.
beta-Nucleoside triphosphate, which arises primarily from beta-ATP, was 16% lower in the depressed subjects than in the comparison subjects.
The low level of beta-nucleoside triphosphate is consistent with an abnormality of high-energy phosphate metabolism in the basal ganglia of subjects with major depression.
The relationship between brain structure and complex behavior is governed by large-scale neurocognitive networks. The availability of a noninvasive technique that can visualize the neuronal projections connecting the functional centers should therefore provide new keys to the understanding of brain function. By using high-resolution three-dimensional diffusion magnetic resonance imaging and a newly designed tracking approach, we show that neuronal pathways in the rat brain can be probed in situ. The results are validated through comparison with known anatomical locations of such fibers.
Studies of depressed adults have shown abnormalities in cerebral energy metabolism, as noted by low brain levels of nucleoside triphosphate (NTP), which primarily represents adenosine triphosphate (ATP). This study was undertaken to determine whether proton magnetic resonance spectroscopy (1H MRS) measures of the low-field purine resonance, which arises primarily from adenosine phosphates, can be used to assess abnormalities in cerebral purine metabolism in depressed adults.
Data from 1H MRS and phosphorus-31 (31P) MRS were acquired for depressed and nondepressed comparison subjects. Intensities of the purine resonance, by 1H MRS (7.5-8.5 ppm), and of NTP, by 31P MRS, were determined.
Purine resonance intensities did not differ on average between depressed patients and comparison subjects. However, purine levels were approximately 30% lower in female depressed subjects who subsequently responded to fluoxetine treatment than in those who did not respond. Beta-NTP was lower by 21% in responders than in nonresponders and was correlated with purine levels for the depressed subjects.
Brain purine levels are low in female depressed patients who respond to treatment with fluoxetine, suggesting that response to treatment might be predicted by using 1H MRS. These observations also suggest that agents that increase brain adenosine levels may have antidepressant efficacy.
Magnetic resonance spectroscopic imaging (MRSI) permits a noninvasive, in vivo assessment of metabolites in the tissue of interest. This chapter primarily reviews the role of proton MRSI in brain tumors and prostate cancer for detection, grading, treatment selection, and assessment of treatment response and prognosis. It reveals that proton MRSI may be a promising adjunct to MRI for better diagnostic and prognostic applications in oncology.
The relationship between brain structure and complex behavior is governed by large-scale neurocognitive networks. The availability of a noninvasive technique that can visualize the neuronal projections connecting the functional centers should therefore provide new keys to the understanding of brain function. By using high-resolution three-dimensional diffusion magnetic resonance imaging and a newly designed tracking approach, we show that neuronal pathways in the rat brain can be probed in situ. The results are validated through comparison with known anatomical locations of such fibers. Ann Neurol 1999;45:265–269
This chapter focuses on application of magnetic resonance spectroscopy (MRS) methodologies and their relevance to drug addiction research. It introduces the significant features and characteristics of currently available MRS techniques and summarizes empirical findings. It outlines limitations of current MRS approaches and highlights potential future research directions to provide an enhanced understanding of brain mechanisms that underlie addiction. Functional and structural alterations observed in neuroimaging studies support conclusion that chronic exposure to alcohol results in neurotoxic effects on brain. The chapter reviews a number of MRS studies for neurometabolite quantification and localization in each patient group dependent on different classes of substance. Ongoing and future studies to expand the use of MRS findings as a potential surrogate biomarker have unique clinical benefits.
Significance
To investigate the organizational principles of human brain development, we analyzed cerebral structural connectivity in the period leading up to the time of normal birth. We found that a “rich club” of interconnected cortical hubs previously reported in adults is present by 30 wk gestation. From mid to late gestation, connections between core hubs and the rest of the brain increased significantly. To determine the influence of environmental factors on network development, we also compared term-born infants to those born prematurely. Alterations in cortical–subcortical connectivity and short-distance connections outside the core network were associated with prematurity. Rich-club organization in the human brain precedes the emergence of complex neurological function, and alterations during this time may impact negatively on subsequent neurodevelopment.
Background:
Major depressive disorder (MDD) has been shown to be associated with a disrupted topological organization of functional brain networks. However, little is known regarding whether these changes have a structural basis. Diffusion tensor imaging (DTI) enables comprehensive whole-brain mapping of the white matter tracts that link regions distributed throughout the entire brain, the so-called human connectome.
Methods:
We examined whole-brain structural networks in a cohort of 95 MDD outpatients and 102 matched control subjects. Structural networks were represented by an 84 × 84 connectivity matrix representing probabilistic white matter connections between 84 parcellated cortical and subcortical regions using DTI tractography. Network-based statistics were used to assess differences in the interregional connectivity matrix between the two groups, and graph theory was used to examine overall topological organization.
Results:
Our network-based statistics analysis demonstrates lowered structural connectivity within two distinct brain networks that are present in depression: the first primarily involves the regions of the default mode network and the second comprises the frontal cortex, thalamus, and caudate regions that are central in emotional and cognitive processing. These two altered networks were observed in the context of an overall preservation of topology as reflected as no significant group differences for the graph-theory measures.
Conclusions:
This is the first report to use DTI to show the structural connectomic alterations present in MDD. Our findings highlight that altered structural connectivity between nodes of the default mode network and the frontal-thalamo-caudate regions are core neurobiological features associated with MDD.
Over the past two decades, many magnetic resonance spectroscopy (MRS) studies reported lower N-acetylaspartate (NAA) in key brain regions of patients with schizophrenia (SZ) compared to healthy subjects. A smaller number of studies report no difference in NAA. Many sources of variance may contribute to these discordant results including heterogeneity of the SZ subject populations and methodological differences such as MRS acquisition parameters, and post-acquisition analytic methods. The current study reviewed proton MRS literature reporting measurements of NAA in SZ with a focus on methodology. Studies which reported lower NAA were significantly more likely to have used longer echo times (TEs), while studies with shorter TEs reported no concentration difference. This suggests that NAA quantitation using MRS was affected by the choice of TE, and that published MRS literature reporting NAA in SZ using a long TE is confounded by apparent differential T2 relaxation effects between SZ and healthy control groups. Future MRS studies should measure T2 relaxation times. This would allow for spectral concentration measurements to be appropriately corrected for these relaxation effects. In addition, as metabolite concentration and T2 relaxation times are completely independent variables, this could offer distinct information about the metabolite of interest.
Background:
Major depressive disorder (MDD) is characterized by abnormalities in structure, function, and connectivity in several brain regions. Few studies have examined how these regions are organized in the brain or investigated network-level structural aberrations that might be associated with depression.
Methods:
We used graph analysis to examine the gray matter structural networks of individuals diagnosed with MDD (n = 93) and a demographically similar healthy comparison group (n = 151) with no history of psychopathology. The efficiency of structural networks for processing information was determined by quantifying local interconnectivity (clustering) and global integration (path length). We also compared the groups on the contributions of high-degree nodes (i.e., hubs) and regional network measures, including degree (number of connections in a node) and betweenness (fraction of short path connections in a node).
Results:
Depressed participants had significantly decreased clustering in their brain networks across a range of network densities. Compared with control subjects, depressed participants had fewer hubs primarily in medial frontal and medial temporal areas, had higher degree in the left supramarginal gyrus and right gyrus rectus, and had higher betweenness in the right amygdala and left medial orbitofrontal gyrus.
Conclusions:
Networks of depressed individuals are characterized by a less efficient organization involving decreased regional connectivity compared with control subjects. Regional connections in the amygdala and medial prefrontal cortex may play a role in maintaining or adapting to depressive pathology. This is the first report of anomalous large-scale gray matter structural networks in MDD and provides new insights concerning the neurobiological mechanisms associated with this disorder.
Context Neural substrates that may be responsible for the high prevalence of depression in type 1 diabetes mellitus (T1DM) have not yet been elucidated.
Objective To investigate neuroanatomic correlates of depression in T1DM.
Design Case-control study using high-resolution brain magnetic resonance images.
Settings Joslin Diabetes Center and McLean Hospital, Massachusetts, and Seoul National University Hospital, South Korea.
Participants A total of 125 patients with T1DM (44 subjects with ≥1 previous depressive episodes [T1DM-depression group] and 81 subjects who had never experienced depressive episodes [T1DM-only group]), 23 subjects without T1DM but with 1 or more previous depressive episodes (depression group), and 38 healthy subjects (control group).
Main Outcome Measures Spatial distributions of cortical thickness for each diagnostic group were compared with the control group using a surface-based approach. Among patients with T1DM, associations between metabolic control measures and cortical thickness deficits were examined.
Results Thickness reduction in the bilateral superior prefrontal cortical regions was observed in the T1DM-depression, T1DM-only, and depression groups relative to the control group at corrected P < .01. Conjunction analyses demonstrated that thickness reductions related to the influence of T1DM and those related to past depressive episode influence were observed primarily in the superior prefrontal cortical region. Long-term glycemic control levels were associated with superior prefrontal cortical deficits in patients with T1DM (β = −0.19, P = .02).
Conclusions This study provides evidence that thickness reduction of prefrontal cortical regions in patients with T1DM, as modified by long-term glycemic control, could contribute to the increased risk for comorbid depression.
The LCModel method analyzes an in vivo spectrum as a Linear Combination of Model in vitro spectra from individual metabolite solutions. Complete model spectra, rather than individual resonances, are used in order to incorporate maximum prior information into the analysis. A nearly model‐free constrained regularization method automatically accounts for the baseline and lineshape in vivo without imposing a restrictive parameterized form on them. LCModel is automatic (non‐interactive) with no subjective input. Approximately maximum‐likelihood estimates of the metabolite concentrations and their uncertainties (Cramér‐Rao lower bounds) are obtained. LCModel analyses of spectra from users with fields from 1.5 to 9.4 T and a wide range of sequences, particularly with short TE , are used here to illustrate the capabilities and limitations of LCModel and proton MRS. Copyright © 2001 John Wiley & Sons, Ltd.
Abbreviations used
Ala alanine
Asp aspartate
Cr creatine
GABA γ‐aminobutyric acid
Glc glucose
Gln glutamine
Glu glutamate
GPC glycerophosphocholine
GSH glutathione
Ins myo ‐inositol
Lac lactate
NAA N ‐acetylaspartate
NAAG N ‐acetylaspartylglutamate
PC phosphocholine
PCr phosphocreatine
PE phosphoethanolamine
Scyllo scyllo ‐inositol
S/N signal‐to‐noise ratio
Tau taurine.
In this Seminar we discuss developments from the past 5 years in the diagnosis, neurobiology, and treatment of major depressive disorder. For diagnosis, psychiatric and medical comorbidity have been emphasised as important factors in improving the appropriate assessment and management of depression. Advances in neurobiology have also increased, and we aim to indicate genetic, molecular, and neuroimaging studies that are relevant for assessment and treatment selection of this disorder. Further studies of depression-specific psychotherapies, the continued application of antidepressants, the development of new treatment compounds, and the status of new somatic treatments are also discussed. We address two treatment-related issues: suicide risk with selective serotonin reuptake inhibitors, and the safety of antidepressants in pregnancy. Although clear advances have been made, no fully satisfactory treatments for major depression are available.
Major Depressive Disorder (MDD) involves deficits in the reward system. While neuroimaging studies have focused on affective stimulus processing, few investigations have directly addressed deficits in the anticipation of incentives. We examined neural responses during gain and loss anticipation in patients with MDD before and after treatment with a selective serotonin reuptake inhibitor (SSRI). Fifteen adults with MDD and 15 healthy participants, matched for age, verbal IQ and smoking habits, were investigated in a functional magnetic resonance imaging (fMRI) study using a monetary incentive delay task. Patients were scanned drug-free and after 6 weeks of open-label treatment with escitalopram; controls were scanned twice at corresponding time points. We compared the blood oxygenation level dependent (BOLD) response during the anticipation of gain and loss with a neutral condition. A repeated measures ANOVA was calculated to identify effects of group (MDD vs. controls), time (first vs. second scan) and group-by-time interaction. Severity of depression was measured with the Hamilton Rating Scale of Depression and the Beck Depression Inventory. MDD patients showed significantly less ventral striatal activation during anticipation of gain and loss compared with controls before, but not after, treatment. There was a significant group-by-time interaction during anticipation of loss in the left ventral striatum due to a signal increase in patients after treatment. Ventral striatal hyporesponsiveness was associated with the severity of depression and in particular anhedonic symptoms. These findings suggest that MDD patients show ventral striatal hyporesponsiveness during incentive cue processing, which normalizes after successful treatment.
Adolescent major depressive disorder (MDD) is a life-threatening brain disease with limited interventions. Treatment resistance is common, and the illness burden is disproportionately borne by females. 31-Phosphorus magnetic resonance spectroscopy ((31)P MRS) is a translational method for in vivo measurement of brain energy metabolites.
We recruited 5 female adolescents who had been on fluoxetine (Prozac®) for ≥ 8 weeks, but continued meet diagnostic criteria for MDD with a Children's Depression Rating Scale-Revised (CDRS-R) raw score ≥ 40. Treatment response was measured with the CDRS-R. (31)P MRS brain scans were performed at baseline, and repeated following adjunctive creatine 4 g daily for 8 weeks. For comparison, 10 healthy female adolescents underwent identical brain scans performed 8 weeks apart.
The mean CDRS-R score declined from 69 to 30.6, a decrease of 56%. Participants experienced no Serious Adverse Events, suicide attempts, hospitalizations or intentional self-harm. There were no unresolved treatment-emergent adverse effects or laboratory abnormalities. MDD participants' baseline CDRS-R score was correlated with baseline pH (p=0.04), and was negatively correlated with beta-nucleoside triphosphate (β-NTP) concentration (p=0.03). Compared to healthy controls, creatine-treated adolescents demonstrated a significant increase in brain Phosphocreatine (PCr) concentration (p=0.02) on follow-up (31)P MRS brain scans.
Lack of placebo control; and small sample size.
Further study of creatine as an adjunctive treatment for adolescents with SSRI-resistant MDD is warranted.
Neuroimaging studies have shown that major depressive disorder (MDD) is accompanied by structural and functional abnormalities in specific brain regions and connections; yet, little is known about alterations of the topological organization of whole-brain networks in MDD patients.
Thirty drug-naive, first-episode MDD patients and 63 healthy control subjects underwent a resting-state functional magnetic resonance imaging scan. The whole-brain functional networks were constructed by thresholding partial correlation matrices of 90 brain regions, and their topological properties (e.g., small-world, efficiency, and nodal centrality) were analyzed using graph theory-based approaches. Nonparametric permutation tests were further used for group comparisons of topological metrics.
Both the MDD and control groups showed small-world architecture in brain functional networks, suggesting a balance between functional segregation and integration. However, compared with control subjects, the MDD patients showed altered quantitative values in the global properties, characterized by lower path length and higher global efficiency, implying a shift toward randomization in their brain networks. The MDD patients exhibited increased nodal centralities, predominately in the caudate nucleus and default-mode regions, including the hippocampus, inferior parietal, medial frontal, and parietal regions, and reduced nodal centralities in the occipital, frontal (orbital part), and temporal regions. The altered nodal centralities in the left hippocampus and the left caudate nucleus were correlated with disease duration and severity.
These results suggest that depressive disorder is associated with disruptions in the topological organization of functional brain networks and that this disruption may contribute to disturbances in mood and cognition in MDD patients.
Epidemiological, neuropathological, and functional neuroimaging evidence implicates global and regional disruptions in brain metabolism and energetics in the pathogenesis of cognitive impairment. Nerve cell microcircuits are modified by excitatory and inhibitory synaptic activity and neurotrophic factors. Ageing and Alzheimer's disease cause perturbations in cellular energy metabolism, level of excitation or inhibition, and neurotrophic factor release, which overwhelm compensatory mechanisms and result in dysfunction of neuronal microcircuits and brain networks. A prolonged positive energy balance impairs the ability of neurons to adapt to oxidative and metabolic stress. Results from experimental studies in animals show how disruptions caused by chronic positive energy balance, such as diabetes, lead to accelerated cognitive ageing and Alzheimer's disease. Therapeutic interventions to allay cognitive dysfunction that target energy metabolism and adaptive stress responses (such as neurotrophin signalling) have been effective in animal models and in preliminary studies in humans.
There are substantial abnormalities in the number, density, and size of cortical neurons and glial cells in bipolar disorder and schizophrenia. Because molecule-microenvironment interactions modulate metabolite signals characteristics, these cellular abnormalities may impact transverse (T2) relaxation times. We measured T2 relaxation times for three intracellular metabolites (N-acetylaspartate+N-acetylaspartylglutamate, creatine+phosphocreatine, and choline-containing compounds) in the anterior cingulate cortex and parieto-occipital cortex from 20 healthy subjects, 15 patients with bipolar disorder, and 15 patients with schizophrenia at 4 T. Spectra used in T2 quantification were collected from 8-cc voxels with varying echo times (30 to 500 ms, in 10-ms steps). Both bipolar disorder and schizophrenia groups had numerically shorter T2 relaxation times than the healthy subjects group in both regions; these differences reached statistical significance for creatine+phosphocreatine and choline-containing compounds in bipolar disorder and for choline-containing compounds in schizophrenia. Metabolite T2 relaxation time shortening is consistent with reduced cell volumes and altered macromolecule structures, and with prolonged water T2 relaxation times reported in bipolar disorder and schizophrenia. These findings suggest that metabolite concentrations reported in magnetic resonance spectroscopy studies of psychiatric conditions may be confounded by T2 relaxation and highlight the importance of measuring and correcting for this variable.
Brain connectivity datasets comprise networks of brain regions connected by anatomical tracts or by functional associations. Complex network analysis-a new multidisciplinary approach to the study of complex systems-aims to characterize these brain networks with a small number of neurobiologically meaningful and easily computable measures. In this article, we discuss construction of brain networks from connectivity data and describe the most commonly used network measures of structural and functional connectivity. We describe measures that variously detect functional integration and segregation, quantify centrality of individual brain regions or pathways, characterize patterns of local anatomical circuitry, and test resilience of networks to insult. We discuss the issues surrounding comparison of structural and functional network connectivity, as well as comparison of networks across subjects. Finally, we describe a Matlab toolbox (http://www.brain-connectivity-toolbox.net) accompanying this article and containing a collection of complex network measures and large-scale neuroanatomical connectivity datasets.
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.
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.
Cross-sectional study.
General clinical research center.
One hundred twenty-three patients with adult type 1 diabetes with varying degrees of lifetime glycemic control and 38 healthy participants.
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.
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.
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.
White matter abnormalities constitute one element of the network dysfunction that underlies affective disorders: differences between the white matter of subjects with affective disorders and control subjects have been identified using a range of neuroimaging and histological techniques. Diffusion tensor imaging (DTI) can uniquely study the orientation and integrity of white matter tracts and is thus an ideal tool to shed light on white matter abnormalities in subjects with affective disorders. Here, we systematically review DTI studies of affective disorders. We identified DTI studies of affective disorders from EMBASE and MEDLINE and searched the reference lists of relevant papers. Twenty-seven articles comparing subjects with affective disorders with control subjects were included in the review, with eight studies included in a meta-analysis of superior frontal regions. Twenty-one of 27 studies found significantly lower anisotropy in subjects with affective disorders compared with control subjects, more specifically within the frontal and temporal lobes or tracts. A large effect size was detected within the superior frontal gyrus, although heterogeneity and one index of publication bias were significant. Although there is significant heterogeneity of acquisition and analysis methods and subject properties, DTI studies of affective disorders consistently identify reduced anisotropy in the frontal and temporal lobes and tracts of subjects with affective disorders relative to control subjects.
Substantial evidence indicates bioenergetic dysfunction and mitochondrial impairment contribute either directly and/or indirectly to the pathogenesis of numerous neurodegenerative disorders. Treatment paradigms aimed at ameliorating this cellular energy deficit and/or improving mitochondrial function in these neurodegenerative disorders may prove to be useful as a therapeutic intervention. Creatine is a molecule that is produced both endogenously, and acquired exogenously through diet, and is an extremely important molecule that participates in buffering intracellular energy stores. Once creatine is transported into cells, creatine kinase catalyzes the reversible transphosphorylation of creatine via ATP to enhance the phosphocreatine energy pool. Creatine kinase enzymes are located at strategic intracellular sites to couple areas of high energy expenditure to the efficient regeneration of ATP. Thus, the creatine kinase/phosphocreatine system plays an integral role in energy buffering and overall cellular bioenergetics. Originally, exogenous creatine supplementation was widely used only as an ergogenic aid to increase the phosphocreatine pool within muscle to bolster athletic performance. However, the potential therapeutic value of creatine supplementation has recently been investigated with respect to various neurodegenerative disorders that have been associated with bioenergetic deficits as playing a role in disease etiology and/or progression which include; Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease. This review discusses the contribution of mitochondria and bioenergetics to the progression of these neurodegenerative diseases and investigates the potential neuroprotective value of creatine supplementation in each of these neurological diseases. In summary, current literature suggests that exogenous creatine supplementation is most efficacious as a treatment paradigm in Huntington's and Parkinson's disease but appears to be less effective for ALS and Alzheimer's disease.
This report provides histopathological evidence to support prior neuroimaging findings of decreased volume and altered metabolism in the frontal cortex in major depressive disorder.
Computer-assisted three-dimensional cell counting was used to reveal abnormal cytoarchitecture in left rostral and caudal orbitofrontal and dorsolateral prefrontal cortical regions in subjects with major depression as compared to psychiatrically normal controls.
Depressed subjects had decreases in cortical thickness, neuronal sizes, and neuronal and glial densities in the upper (II-IV) cortical layers of the rostral orbitofrontal region. In the caudal orbitofrontal cortex in depressed subjects, there were prominent reductions in glial densities in the lower (V-VI) cortical layers that were accompanied by small but significant decreases in neuronal sizes. In the dorsolateral prefrontal cortex of depressed subjects marked reductions in the density and size of neurons and glial cells were found in both supra- and infragranular layers.
These results reveal that major depression can be distinguished by specific histopathology of both neurons and glial cells in the prefrontal cortex. Our data will contribute to the interpretation of neuroimaging findings and identification of dysfunctional neuronal circuits in major depression.
Functional neuroimaging studies of the anatomical correlates of familial major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of resting blood flow (BF) and glucose metabolism in depression in the amygdala and the orbital and medial prefrontal cortical (PFC) areas that are extensively connected with the amygdala. The amygdala metabolism in MDD and BD is positively correlated with both depression severity and "stressed" plasma cortisol concentrations measured during scanning. During antidepressant drug treatment, the mean amygdala metabolism decreases in treatment responders, and the persistence of elevated amygdala metabolism during remission is associated with a high risk for the development of depressive relapse. The orbital C metabolism is also abnormally elevated during depression, but is negatively correlated with both depression severity and amygdala metabolism, suggesting that this structure may be activated as a compensatory mechanism to modulate amygdala activity or amygdala-driven emotional responses. The posterior orbital C and anterior cingulate C ventral to the genu of the corpus callosum (subgenual PFC) have more recently been shown in morphometric MRI and/or post mortem histopathological studies to have reduced grey matter volume and reduced glial cell numbers (with no equivalent loss of neurons) in familial MDD and BD. These data suggest a neural model in which dysfunction of limbic PFC structures impairs the modulation of the amygdala, leading to abnormal processing of emotional stimuli. Antidepressant drugs may compensate for this dysfunction by inhibiting pathological limbic activity.
Outcomes research in bipolar disorders, because of complex clinical variation over-time, offers demanding research design and statistical challenges. Longitudinal studies involving relatively large samples, with outcome measures obtained repeatedly over-time, are required. In this report, statistical methods appropriate for such research are reviewed.
Analytic methods appropriate for repeated measures data include: (i) endpoint analysis; (ii) endpoint analysis with last observation carried forward; (iii) summary statistic methods yielding one summary measure per subject; (iv) random effects and generalized estimating equation (GEE) regression modeling methods; and (v) time-to-event survival analyses.
Use and limitations of these several methods are illustrated within a randomly selected (33%) subset of data obtained in two recently completed randomized, double blind studies on acute mania. Outcome measures obtained repeatedly over 3 or 4 weeks of blinded treatment in active drug and placebo sub-groups included change-from-baseline Young Mania Rating Scale (YMRS) scores (continuous measure) and achievement of a clinical response criterion (50% YMRS reduction). Four of the methods reviewed are especially suitable for use with these repeated measures data: (i) the summary statistic method; (ii) random/mixed effects modeling; (iii) GEE regression modeling; and (iv) survival analysis.
Outcome studies in bipolar illness ideally should be longitudinal in orientation, obtain outcomes data frequently over extended times, and employ large study samples. Missing data problems can be expected, and data analytic methods must accommodate missingness.
Alterations in brain high-energy phosphate metabolism, determined by in vivo magnetic resonance spectroscopy (MRS), have been reported in subjects with a number of brain disorders including major depression, schizophrenia, and substance abuse. It is not clear to what extent these changes can be modified by pharmacological or nutritional means. To address this possibility, we evaluated changes in brain chemistry that were associated with oral creatine (Cr) administration. We hypothesized that oral Cr supplementation, by increasing brain creatine and high-energy phosphate stored in phosphocreatine, would result in an increase in the creatine resonance, as measured using proton 1H-MRS, and a decrease in the beta-nucleoside triphosphate (NTP) peak and an increase in the phosphocreatine (PCr) peak, as measured by phosphorus 31P-MRS, in brain of healthy human subjects. Fifteen healthy male subjects (age=22.9+/-2.2; body mass index=22.9+/-1.7), who were without any axis I disorders or physical or neurological illness, were recruited. Ten subjects took creatine-monohydrate, 0.3 g/kg/day for the first 7 days and 0.03 g/kg/day for the next 7 days (creatine group). Five comparison subjects took equivalent amounts of sucrose as placebo (placebo group). Both 1H- and 31P-MRS scans were acquired at baseline, as well as at day 7 and day 14 of oral supplementation. 1H-MRS: Water suppressed localized spectra were acquired using a single-voxel (1.5 cm x 2 cm x 2 cm) proton MRS PRESS sequence in the left frontal lobe. 31P-MRS: Phosphorus spectral data were recorded from a 5-cm-thick axial brain slice using a short-TE slice selective spin-echo pulse sequence. The creatine group had significantly increased brain creatine levels (8.1% and 9.3%, in creatine/N-acetyl aspartate and creatine/choline ratios, respectively) compared to the placebo group over the 2-week period. The creatine group had significantly decreased beta-NTP levels (7.8%) and marginally increased PCr (3.4%) over the same period. In addition, the brain inorganic phosphate level increased over the same period in the creatine group (9.8%). The current study is the first multinuclear (1H and 31P) MRS study to evaluate changes in brain high-energy phosphate metabolism following oral creatine supplementation in healthy human subjects. These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders, including major depression, schizophrenia, cocaine and opiate abuse, where alterations in brain high-energy phosphate metabolism have been reported.
The authors used magnetic resonance spectroscopy (MRS) to assess the effect of acute administration of the selective serotonin reuptake inhibitor (SSRI) citalopram on cortical levels of gamma-aminobutyric acid (GABA).
Ten healthy volunteers received either intravenous citalopram (10 mg) or saline in a randomized, double-blind, crossover design. The occipital GABA/creatine ratio was measured with a proton MR spectral editing technique.
In comparison with saline, citalopram produced a mean increase of 35% in relative brain GABA concentration in the occipital cortex.
These findings extend previous work showing that SSRI treatment increases cortical GABA in depressed patients and suggest that this results from an action of SSRIs on GABA neurons rather than as a secondary consequence of mood improvement.