Studies on magnetism and bioelectromagnetics for 45 years: from magnetic analog memory to human brain stimulation and imaging

Forty-five years of studies on magnetism and bioelectromagnetics, in our laboratory, are presented. This article is prepared for the d'Arsonval Award Lecture. After a short introduction of our early work on magnetic analog memory, we review and discuss the following topics: (1) Magnetic nerve stimulation and localized transcranial magnetic stimulation (TMS) of the human brain by figure-eight coils; (2) Measurements of weak magnetic fields generated from the brain by superconducting quantum interference device (SQUID) systems, called magnetoencephalography (MEG), and its application in functional brain studies; (3) New methods of magnetic resonance imaging (MRI) for the imaging of impedance of the brain, called impedance MRI, and the imaging of neuronal current activities in the brain, called current MRI; (4) Cancer therapy and other medical treatments by pulsed magnetic fields; (5) Effects of static magnetic fields and magnetic control of cell orientation and cell growth; and (6) Effects of radio frequency magnetic fields and control of iron ion release and uptake from and into ferritins, iron cage proteins. These bioelectromagnetic studies have opened new horizons in magnetism and medicine, in particular for brain research and treatment of ailments such as depression, Parkinson's, and Alzheimer's diseases.     

Magnetic nanoparticles for multi-imaging and drug delivery

Various bio-medical applications of magnetic nanoparticles have been explored during the past few decades. As tools that hold great potential for advancing biological sciences, magnetic nanoparticles have been used as platform materials for enhanced magnetic resonance imaging (MRI) agents, biological separation and magnetic drug delivery systems, and magnetic hyperthermia treatment. Furthermore, approaches that integrate various imaging and bioactive moieties have been used in the design of multi-modality systems, which possess synergistically enhanced properties such as better imaging resolution and sensitivity, molecular recognition capabilities, stimulus responsive drug delivery with on-demand control, and spatio-temporally controlled cell signal activation. Below, recent studies that focus on the design and synthesis of multi-mode magnetic nanoparticles will be briefly reviewed and their potential applications in the imaging and therapy areas will be also discussed.     

帕金森病合并抑郁与脑血流灌注的关系及经颅磁刺激的影响

目的：应用CT灌注成像技术观察帕金森病合并抑郁患者局灶脑血流灌注的特点,进一步探讨抑郁症发生与脑血流的关系.方法：将41例帕金森患者根据是否合并抑郁症分为帕金森病组22例、帕金森病合并抑郁症者为抑郁组19例、其中抑郁组分为经颅磁刺激（rTMS）治疗前组、治疗后组,3组均进行CT局部脑血流灌注显像,半定量分析各脑区血流灌注情况.结果：帕金森合并抑郁症组患者双侧额叶、颞叶和基底节的脑血流量测定（CBF）较帕金森病组显著下降（P＜0.05）;抑郁组左、右侧脑血流低灌注存在不对称性,左侧额叶、顶叶的CBF较右侧显著下降（P＜0.01）;rTMS治疗后脑血流灌注较治疗前改善,HAMD评分改善（P＜0.05）.结论：帕金森患者存在局灶性脑血流灌注降低,合并抑郁症患者额、顶叶下降更明显,经颅磁刺激治疗后脑血流低灌注改善.     

Deep brain stimulation for treatment-resistant depression

Treatment-resistant depression is a severely disabling disorder with no proven treatment options once multiple medications, psychotherapy, and electroconvulsive therapy have failed. Based on our preliminary observation that the subgenual cingulate region (Brodmann area 25) is metabolically overactive in treatment-resistant depression, we studied whether the application of chronic deep brain stimulation to modulate BA25 could reduce this elevated activity and produce clinical benefit in six patients with refractory depression. Chronic stimulation of white matter tracts adjacent to the subgenual cingulate gyrus was associated with a striking and sustained remission of depression in four of six patients. Antidepressant effects were associated with a marked reduction in local cerebral blood flow as well as changes in downstream limbic and cortical sites, measured using positron emission tomography. These results suggest that disrupting focal pathological activity in limbic-cortical circuits using electrical stimulation of the subgenual cingulate white matter can effectively reverse symptoms in otherwise treatment-resistant depression.     

基于精神影像和人工智能的抑郁症客观生物学标志物研究进展

抑郁症是当今社会上造成首要危害且病因和病理机制最为复杂的精神疾病之一,寻找抑郁症的客观生物学标志物一直是精神医学研究和临床实践的重点和难点,而结合人工智能技术的磁共振影像(magnetic resonance imaging,MRI)技术被认为是目前抑郁症等精神疾病中最有可能率先取得突破进展的客观生物学标志物.然而,当前基于精神影像学的潜在抑郁症客观生物学标志物还未得到一致结论 .本文从精神影像学和以机器学习(machine learning,ML)与深度学习(deep learning, DL)等为代表的人工智能技术相结合的角度,首次从疾病诊断、预防和治疗等三大临床实践环节对抑郁症辅助诊疗的相关研究进行归纳分析,我们发现:a.具有诊断价值的脑区主要集中在楔前叶、扣带回、顶下缘角回、脑岛、丘脑以及海马等;b.具有预防价值的脑区主要集中在楔前叶、中央后回、背外侧前额叶、眶额叶、颞中回等;c.具有预测治疗反应价值的脑区主要集中在楔前叶、扣带回、顶下缘角回、额中回、枕中回、枕下回、舌回等.未来的研究可以通过多中心协作和数据变换提高样本量,同时将多元化的非影像学数据应用于数据挖掘,这将有利于提高人工智能模型的辅助分类能力,为探寻抑郁症的精神影像学客观生物学标志物及其临床应用提供科学证据和参考依据.     

Exploring the effect of chronotype on hippocampal volume and shape: A combined approach

Current evidence suggests that acute depression is associated with reduced total hippocampal volume and regional atrophy. Here, using structural magnetic resonance imaging, we assayed linear effects of chronotype on total hippocampal volume and morphology. Later chronotype was associated with localised atrophy in the subiculum region of the right hippocampus in the absence of changes in total volume. The hippocampus forms a key node in a network of brain regions implicated in emotional regulation and alterations in the structure of this region may underpin, in part, the increased vulnerability for depression in late chronotype individuals.     

光疗及光照剂量对抑郁症的作用研究进展

抑郁症是一种患病率高、易复发、自杀率高的精神障碍疾病，容易导致认知功能损伤等问题. 光疗以无创、副作用小、疗效快等优势受到广泛的关注，为调节抑郁症生物节律和睡眠障碍等症状提供了新的可能性. 光信号通过视网膜神经节细胞投射到抑郁脑区参与非视觉成像功能，激活神经细胞活动，分泌神经递质使神经通路产生生理性改变，对生物机体的昼夜节律、情绪、睡眠产生调控作用，达到改善抑郁行为的目的. 光的波长、剂量和最佳作用模式与治疗效果息息相关，但目前光疗的最佳应用模式仍存在争议. 为了全面促进光疗在生命科学领域以及临床上的应用，仍需进行大量的临床与模型动物光学参数研究. 本文从光疗路径、不同光谱作用机制、光学参数、作用疗效、存在问题及展望进行综述，促进光疗调控抑郁症的深入研究.     

Le diagnostic et le suivi thérapeutique des tumeurs cérébrales intra-parenchymateuses par l’imagerie par résonance magnétique multimodale

The multimodal magnetic resonance imaging (MMRI) has an important role in cancer care. This non-invasive and non-ionizing technique provides vital information for the diagnosis and answers to various questions of clinicians before, during and after treatment. The MMRI can specify the localization expanding process; it allows establishing the differential diagnosis of a brain tumor and a circumscribed lesion of another type, to approach the diagnosis of the tumor lesion nature as well as establishing the histological grade of glial tumor in view of lesion monitoring after treatment. The multimodal magnetic resonance imaging has a major contribution to the management progress of the brain tumors. Thus, this paper reviews the value of these MRI modalities in the diagnosis, management and therapy of brain tumors.     

A network meta‐analysis of the effects of psychotherapies,pharmacotherapies and their combination in the treatment of adult depression

No network meta‐analysis has examined the relative effects of psychotherapies, pharmacotherapies and their combination in the treatment of adult depression, while this is a very important clinical issue. We conducted systematic searches in bibliographical databases to identify randomized trials in which a psychotherapy and a pharmacotherapy for the acute or long‐term treatment of depression were compared with each other, or in which the combination of a psychotherapy and a pharmacotherapy was compared with either one alone. The main outcome was treatment response (50% improvement between baseline and endpoint). Remission and acceptability (defined as study drop‐out for any reason) were also examined. Possible moderators that were assessed included chronic and treatment‐resistant depression and baseline severity of depression. Data were pooled as relative risk (RR) using a random‐effects model. A total of 101 studies with 11,910 patients were included. Depression in most studies was moderate to severe. In the network meta‐analysis, combined treatment was more effective than psychotherapy alone (RR=1.27; 95% CI: 1.14‐1.39) and pharmacotherapy alone (RR=1.25; 95% CI: 1.14‐1.37) in achieving response at the end of treatment. No significant difference was found between psychotherapy alone and pharmacotherapy alone (RR=0.99; 95% CI: 0.92‐1.08). Similar results were found for remission. Combined treatment (RR=1.23; 95% CI: 1.05‐1.45) and psychotherapy alone (RR=1.17; 95% CI: 1.02‐1.32) were more acceptable than pharmacotherapy. Results were similar for chronic and treatment‐resistant depression. The combination of psychotherapy and pharmacotherapy seems to be the best choice for patients with moderate depression. More research is needed on long‐term effects of treatments (including cost‐effectiveness), on the impact of specific pharmacological and non‐pharmacological approaches, and on the effects in specific populations of patients.     

Focus: Microbiome: Integrative Therapies in Anxiety Treatment with Special Emphasis on the Gut Microbiome

Over the past decade, research has shown that diet and gut health affects symptoms expressed in stress related disorders, depression, and anxiety through changes in the gut microbiota. Psycho-behavioral function and somatic health interaction have often been ignored in health care with resulting deficits in treatment quality and outcomes. While mental health care requires the professional training in counseling, psychotherapy and psychiatry, complimentary therapeutic strategies, such as attention to a nutritional and diverse diet and supplementation of probiotic foods, may be integrated alongside psychotherapy treatment models. Development of these alternative strategies is predicated on experimental evidence and diligent research on the biology of stress, fear, anxiety-related behaviors, and the gut-brain connection. This article provides a brief overview on biological markers of anxiety and the expanding nutritional literature relating to brain health and mental disorders. A case study demonstrates an example of a biopsychosocial approach integrating cognitive psychotherapy, dietary changes, and mindfulness activities, in treating symptoms of anxiety. This case study shows a possible treatment protocol to explore the efficacy of targeting the gut-brain-axis that may be used as an impetus for future controlled studies.     

Serotonergic genes modulate amygdala activity in major depression

Serotonergic genes have been implicated in the pathogenesis of depression probably via their influence on neural activity during emotion processing. This study used an imaging genomics approach to investigate amygdala activity in major depression as a function of common functional polymorphisms in the serotonin transporter gene (5-HTTLPR) and the serotonin receptor 1A gene (5-HT(1A)-1019C/G). In 27 medicated patients with major depression, amygdala responses to happy, sad and angry faces were assessed using functional magnetic resonance imaging at 3 Tesla. Patients were genotyped for the 5-HT(1A)-1019C/G and the 5-HTTLPR polymorphism, including the newly described 5-HTT-rs25531 single nucleotide polymorphism. Risk allele carriers for either gene showed significantly increased bilateral amygdala activation in response to emotional stimuli, implicating an additive effect of both genotypes. Our data suggest that the genetic susceptibility for major depression might be transported via dysfunctional neural activity in brain regions critical for emotion processing.     

Magnetic resonance imaging for chronic pain: diagnosis,manipulation, and biomarkers

Pain is a multidimensional subjective experience with biological, psychological, and social factors. Whereas acute pain can be a warning signal for the body to avoid excessive injury, long-term and ongoing pain may be developed as chronic pain. There are more than 100 million people in China living with chronic pain, which has raised a huge socioeconomic burden. Studying the mechanisms of pain and developing effective analgesia approaches are important for basic and clinical research. Recently, with the development of brain imaging and data analytical approaches, the neural mechanisms of chronic pain have been widely studied. In the first part of this review, we briefly introduced the magnetic resonance imaging and conventional analytical approaches for brain imaging data. Then, we reviewed brain alterations caused by several chronic pain disorders, including localized and widespread primary pain, primary headaches and orofacial pain, musculoskeletal pain, and neuropathic pain, and present meta-analytical results to show brain regions associated with the pathophysiology of chronic pain. Next, we reviewed brain changes induced by pain interventions, such as pharmacotherapy, neuromodulation, and acupuncture. Lastly, we reviewed emerging studies that combined advanced machine learning and neuroimaging techniques to identify diagnostic, prognostic, and predictive biomarkers in chronic pain patients.     

Tracking Functional Brain Changes in Patients with Depression under Psychodynamic Psychotherapy Using Individualized Stimuli

Objective

Neurobiological models of depression posit limbic hyperactivity that should normalize after successful treatment. For psychotherapy, though, brain changes in patients with depression show substantial variability. Two critical issues in relevant studies concern the use of unspecific stimulation experiments and relatively short treatment protocols. Therefore changes in brain reactions to individualized stimuli were studied in patients with depression after eight months of psychodynamic psychotherapy.

Methods

18 unmedicated patients with recurrent major depressive disorder were confronted with individualized and clinically derived content in a functional MRI experiment before (T1) and after eight months (T2) of psychodynamic therapy. A control group of 17 healthy subjects was also tested twice without intervention. The experimental stimuli were sentences describing each participant''s dysfunctional interpersonal relationship patterns derived from clinical interviews based on Operationalized Psychodynamic Diagnostics (OPD).

Results

At T1 patients showed enhanced activation compared to controls in several limbic and subcortical regions, including amygdala and basal ganglia, when confronted with OPD sentences. At T2 the differences in brain activity between patients and controls were no longer apparent. Concurrently, patients had improved significantly in depression scores.

Conclusions

Using ecologically valid stimuli, this study supports the model of limbic hyperactivity in depression that normalizes after treatment. Without a control group of untreated patients measured twice, though, changes in patients'' brain activity could also be attributed to other factors than psychodynamic therapy.     

Current imaging paradigms in radiation oncology

The technological revolution in imaging during recent decades has transformed the way image-guided radiation therapy is performed. Anatomical imaging (plain radiography, computed tomography, magnetic resonance imaging) greatly improved the accuracy of delineating target structures and has formed the foundation of 3D-based radiation treatment. However, the treatment planning paradigm in radiation oncology is beginning to shift toward a more biological and molecular approach as advances in biochemistry, molecular biology, and technology have made functional imaging (positron emission tomography, nuclear magnetic resonance spectroscopy, optical imaging) of physiological processes in tumors more feasible and practical. This review provides an overview of the role of current imaging strategies in radiation oncology, with a focus on functional imaging modalities, as it relates to staging and molecular profiling (cellular proliferation, apoptosis, angiogenesis, hypoxia, receptor status) of tumors, defining radiation target volumes, and assessing therapeutic response. In addition, obstacles such as imaging-pathological validation, optimal timing of post-therapy scans, spatial and temporal evolution of tumors, and lack of clinical outcome studies are discussed that must be overcome before a new era of functional imaging-guided therapy becomes a clinical reality.     

Imaging neurodegeneration in Parkinson's disease

Neuroimaging techniques have evolved over the past several years giving us unprecedented information about the degenerative process in Parkinson's disease (PD) and other movement disorders. Functional imaging approaches such as positron emission tomography (PET) and single photon emission computerised tomography (SPECT) have been successfully employed to detect dopaminergic dysfunction in PD, even while at a preclinical stage, and to demonstrate the effects of therapies on function of intact dopaminergic neurons within the affected striatum. PET and SPECT can also monitor PD progression as reflected by changes in brain levodopa and glucose metabolism and dopamine transporter binding. Structural imaging approaches include magnetic resonance imaging (MRI) and transcranial sonography (TCS). Recent advances in voxel-based morphometry and diffusion-weighted MRI have provided exciting potential applications for the differential diagnosis of parkinsonian syndromes. Substantia nigra hyperechogenicity, detected with TCS, may provide a marker of susceptibility to PD, probably reflecting disturbances of iron metabolism, but does not appear to correlate well with disease severity or change with disease progression. In the future novel radiotracers may help us assess the involvement of non-dopaminergic brain pathways in the pathology of both motor and non-motor complications in PD.     

Promising approaches in using magnetic nanoparticles in oncology

The development of new and effective drug delivery systems for cancer treatment represents one of the significant challenges facing biomedical technology in the last decade. Among the different methods of drug delivery, magnetic drug targeting, by enabling specific delivery of chemotherapeutic agents through the use of magnetic nanoparticles and magnetic field gradient, could be a promising approach. Recently, magnetic nanoparticles have attracted additional attention because of their potential as contrast agents for magnetic resonance imaging and heat mediators for cancer therapy. This review summarizes these approaches in the use of magnetic nanoparticles in biomedical applications and novel methods for their optimization.     

Perinatal depression: implications for child mental health

Perinatal depression is common and primary care holds a crucial role for detecting, treating or, if necessary, providing referrals to mental health care for affected women. Family doctors should be aware of risk factors for peripartum depression, including previous history of depression, life events and interpersonal conflict. Perinatal depression has been associated with many poor outcomes, including maternal, child and family unit challenges. Infants and young children of perinatally depressed mothers are more likely to have a difficult temperament, as well as cognitive and emotional delays. The primary care setting is uniquely poised to be the screening and treatment site for perinatal depression; however, several obstacles, both at patient and systems level, have been identified that interfere with women's treatment engagement. Current published treatment guidelines favour psychotherapy above medicines as first line treatment for mild to moderate perinatal depression, while pharmacotherapy is first choice for severe depression, often in combination with psychosocial or integrative approaches. Among mothers who decide to stop taking their antidepressants despite ongoing depression during the perinatal period, the majority suffer from relapsing symptoms. If depression continues post-partum, there is an increased risk of poor mother-infant attachment, delayed cognitive and linguistic skills in the infant, impaired emotional development and risk for behavioural problems in later life. Complex, comprehensive and multilevel algorithms are warranted to treat perinatal depression. Primary care doctors are best suited to initiate, carry out and evaluate the effectiveness of such interventions designed to prevent adverse outcomes of maternal perinatal depression on mother and child wellbeing.     

What has functional connectivity and chemical neuroimaging in fibromyalgia taught us about the mechanisms and management of ‘centralized’ pain?

Research suggests that fibromyalgia is a central, widespread pain syndrome supported by a generalized disturbance in central nervous system pain processing. Over the past decades, multiple lines of research have identified the locus for many functional, chronic pain disorders to the central nervous system, and the brain. In recent years, brain neuroimaging techniques have heralded a revolution in our understanding of chronic pain, as they have allowed researchers to non-invasively (or minimally invasively) evaluate human patients suffering from various pain disorders. While many neuroimaging techniques have been developed, growing interest in two specific imaging modalities has led to significant contributions to chronic pain research. For instance, resting functional connectivity magnetic resonance imaging (fcMRI) is a recent adaptation of fMRI that examines intrinsic brain connectivity - defined as synchronous oscillations of the fMRI signal that occurs in the resting basal state. Proton magnetic resonance spectroscopy (¹H-MRS) is a non-invasive magnetic resonance imaging technique that can quantify the concentration of multiple metabolites within the human brain. This review will outline recent applications of the complementary imaging techniques - fcMRI and ¹H-MRS - to improve our understanding of fibromyalgia pathophysiology and how pharmacological and non-pharmacological therapies contribute to analgesia in these patients. A better understanding of the brain in chronic pain, with specific linkage as to which neural processes relate to spontaneous pain perception and hyperalgesia, will greatly improve our ability to develop novel therapeutics. Neuroimaging will play a growing role in the translational research approaches needed to make this a reality.     

Physiological basis and image processing in functional magnetic resonance imaging: Neuronal and motor activity in brain

Functional magnetic resonance imaging (fMRI) is recently developing as imaging modality used for mapping hemodynamics of neuronal and motor event related tissue blood oxygen level dependence (BOLD) in terms of brain activation. Image processing is performed by segmentation and registration methods. Segmentation algorithms provide brain surface-based analysis, automated anatomical labeling of cortical fields in magnetic resonance data sets based on oxygen metabolic state. Registration algorithms provide geometric features using two or more imaging modalities to assure clinically useful neuronal and motor information of brain activation. This review article summarizes the physiological basis of fMRI signal, its origin, contrast enhancement, physical factors, anatomical labeling by segmentation, registration approaches with examples of visual and motor activity in brain. Latest developments are reviewed for clinical applications of fMRI along with other different neurophysiological and imaging modalities.     

Early microstructural white matter changes in patients with HIV: a diffusion tensor imaging study

ABSTRACT: Previous studies have reported white matter (WM) brain alterations in asymptomatic patients with human immunodeficiency virus (HIV). We compared diffusion tensor imaging (DTI) derived WM fractional anisotropy (FA) between HIV-patients with and without mild macroscopic brain lesions determined using standard magnetic resonance imaging (MRI). We furthermore investigated whether WM alterations co-occurred with neurocognitive deficits and depression. We performed structural MRI and DTI for 19 patients and 19 age-matched healthy controls. Regionally-specific WM integrity was investigated using voxel-based statistics of whole-brain FA maps and region-of-interest analysis. Each patient underwent laboratory and neuropsychological tests. Structural MRI revealed no lesions in twelve (HIV-MRN) and unspecific mild macrostructural lesions in seven patients (HIV-MRL). Both analyses revealed widespread FA-alterations in all patients. Patients with HIV-MRL had FA-alterations primarily adjacent to the observed lesions and, whilst reduced in extent, patients with HIV-MRN also exhibited FA-alterations in similar regions. Patients with evidence of depression showed FA-increase in the ventral tegmental area, pallidum and nucleus accumbens in both hemispheres, and patients with evidence of HIV-associated neurocognitive disorder showed widespread FA-reduction. These results show that patients with HIV-MRN have evidence of FA-alterations in similar regions that are lesioned in HIV-MRL patients, suggesting common neuropathological processes. Furthermore, they suggest a biological rather a reactive origin of depression in HIV-patients.