Changes in Structural Covariance among Olfactory-related Brain Regions in Anosmia Patients

Anosmia, characterized by the loss of smell, is associated not only with dysfunction in the peripheral olfactory system but also with changes in several brain regions involved in olfactory processing. Specifically, the orbitofrontal cortex is recognized for its pivotal role in integrating olfactory information, engaging in bidirectional communication with the primary olfactory regions, including the olfactory cortex, amygdala, and entorhinal cortex. However, little is known about alterations in structural connections among these brain regions in patients with anosmia. In this study, highresolution T1-weighted images were obtained from participants. Utilizing the volumes of key brain regions implicated in olfactory function, we employed a structural covariance approach to investigate brain reorganization patterns in patients with anosmia (n=22) compared to healthy individuals (n=30). Our structural covariance analysis demonstrated diminished connectivity between the amygdala and entorhinal cortex, components of the primary olfactory network, in patients with anosmia compared to healthy individuals (z=-2.22, FDR-corrected p=0.039). Conversely, connectivity between the orbitofrontal cortex—a major region in the extended olfactory network—and amygdala was found to be enhanced in the anosmia group compared to healthy individuals (z=2.32, FDR-corrected p=0.039). However, the structural connections between the orbitofrontal cortex and entorhinal cortex did not differ significantly between the groups (z=0.04, FDR-corrected p=0.968). These findings suggest a potential structural reorganization, particularly of higher-order cortical regions, possibly as a compensatory effort to interpret the limited olfactory information available in individuals with olfactory loss.

Alterations in Brain Morphometric Networks and Their Relationship with Memory Dysfunction in Patients with Type 2 Diabetes Mellitus

Cognitive dysfunction, a significant complication of type 2 diabetes mellitus (T2DM), can potentially manifest even from the early stages of the disease. Despite evidence of global brain atrophy and related cognitive dysfunction in early-stage T2DM patients, specific regions vulnerable to these changes have not yet been identified. The study enrolled patients with T2DM of less than five years’ duration and without chronic complications (T2DM group, n=100) and demographically similar healthy controls (control group, n=50). High-resolution T1-weighted magnetic resonance imaging data were subjected to independent component analysis to identify structurally significant components indicative of morphometric networks. Within these networks, the groups’ gray matter volumes were compared, and distinctions in memory performance were assessed. In the T2DM group, the relationship between changes in gray matter volume within these networks and declines in memory performance was examined. Among the identified morphometric networks, the T2DM group exhibited reduced gray matter volumes in both the precuneus (Bonferronicorrected p=0.003) and insular-opercular (Bonferroni-corrected p=0.024) networks relative to the control group. Patients with T2DM demonstrated significantly lower memory performance than the control group (p=0.001). In the T2DM group, reductions in gray matter volume in both the precuneus (r=0.316, p=0.001) and insular-opercular (r=0.199, p=0.047) networks were correlated with diminished memory performance. Our findings indicate that structural alterations in the precuneus and insular-opercular networks, along with memory dysfunction, can manifest within the first 5 years following a diagnosis of T2DM.

Aberrant Resting-state Functional Connectivity in Complex Regional Pain Syndrome: A Network-based Statistics Analysis

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder. Pain catastrophizing, characterized by magnification, rumination, and helplessness, increases perceived pain intensity and mental distress in CRPS patients. As functional connectivity patterns in CRPS remain largely unknown, we aimed to investigate functional connectivity alterations in CRPS patients and their association with pain catastrophizing using a whole-brain analysis approach. Twenty-one patients with CRPS and 49 healthy controls were included in the study for clinical assessment and resting-state functional magnetic resonance imaging. Between-group differences in whole-brain functional connectivity were examined through a Network-based Statistics analysis. Associations between altered functional connectivity and the extent of pain catastrophizing were also assessed in CRPS patients. Relative to healthy controls, CRPS patients showed higher levels of functional connectivity in the bilateral somatosensory subnetworks (components 1~2), but lower functional connectivity within the prefronto-posterior cingulate (component 3), prefrontal (component 4), prefronto-parietal (component 5), and thalamo-anterior cingulate (component 6) subnetworks (p<0.05, family-wise error corrected). Higher levels of functional connectivity in components 1~2 (β=0.45, p=0.04) and lower levels of functional connectivity in components 3~6 (β=-0.49, p=0.047) were significantly correlated with higher levels of pain catastrophizing in CRPS patients. Higher functional connectivity in the somatosensory subnetworks implicating exaggerated pain perception and lower functional connectivity in the prefronto-parieto-cingulo-thalamic subnetworks indicating impaired cognitive-affective pain processing may underlie pain catastrophizing in CRPS.

Intact Recognition Memory and Altered Hippocampal Glucocorticoid Receptor Signaling in Fkbp5-deficient Mice Following Acute Uncontrollable Stress

The FK506 binding protein 5 (FKBP5) is a co-chaperone that regulates the activity of the glucocorticoid receptor (GR) and has been reported to mediate stress resilience. This study aimed to determine the effects of Fkbp5 deletion on acute stress-induced recognition memory impairment and hippocampal GR signaling. Wild-type and Fkbp5-knockout mice were subjected to acute uncontrollable stress induced by restraint and electrical tail shock. First, we assessed the cognitive status of mice using a novel object recognition task. Next, we measured plasma corticosterone, GR levels, and the levels of GR phosphorylation at serine 211 in the hippocampus. Wild-type mice exhibited stress-induced memory impairments, whereas Fkbp5-knockout mice did not. Plasma corticosterone and GR levels did not differ between the non-stressed wild-type and Fkbp5-knockout mice, but the levels of phosphorylated GR were lower in Fkbp5-knockout mice than in wild-type mice. Wild-type and Fkbp5-knockout mice showed increased nuclear GR levels following stress, indicating GR translocation. However, cytosolic phosphorylated GR levels were lower in the hippocampi of Fkbp5-knockout mice following stress than in those of wild-type mice. These results suggest that FKBP5 deficiency increases resilience to acute stress by altering GR signaling.

A Review on Brain Imaging Studies of Suicide in Youth

Suicide is a leading cause of death worldwide, especially among adolescents and young adults. Considering this fact, it is imperative that we understand the neural mechanisms underlying suicidal thoughts and behaviors in youth from a neurodevelopmental perspective. In this review, we focused on the magnetic resonance imaging studies that examined the neural correlates of suicidal ideations (SI) or attempts (SA) in youth. We reviewed twenty-three cross-sectional studies reporting the structural and functional alterations in association with SI or SA among adolescents and young adults with various mental disorders. The previous literature suggests that the dorsolateral prefrontal cortex, anterior cingulate cortex, and ventral frontolimbic circuit, may play an important role in the pathophysiology of suicidal behavior in youth through altered top-down control over emotion and impulsivity. Future studies with a longitudinal design and using multimodal imaging techniques may be of help to identify novel therapeutic targets specific for youth with suicidal thoughts and behaviors.

A Review of Brain Imaging Studies on Classical Fear Conditioning and Extinction in Healthy Adults

Fear conditioning and extinction, which are adaptive processes to learn and avoid potential threats, have essential roles in the pathophysiology of anxiety disorders. Experimental fear conditioning and extinction have been used to identify the mechanism of fear and anxiety in humans. However, the brain-based mechanisms of fear conditioning and extinction are yet to be established. In the current review, we summarized the results of neuroimaging studies that examined the brain changes—functional activity and structures—regarding fear conditioning or extinction in healthy individuals. The functional activity of the amygdala, insula, anterior cingulate gyrus, ventromedial prefrontal cortex, and hippocampus changed dynamically with both fear conditioning and extinction. This review may provide an up-to-date summary that may broaden our understanding of pathophysiological mechanisms of anxiety disorder. In addition, the brain regions that are involved in the fear conditioning and extinction may be considered as potential treatment targets in the future studies.

A Review on Effects of Non-Invasive Brain Stimulation in the Treatment of Sleep Disorders / 수면정신생리

Sleep disorders, increasingly prevalent in the general population, induce impairment in daytime functioning and other clinical problems. As changes in cortical excitability have been reported as potential pathophysiological mechanisms underlying sleep disorders, multiple studies have explored clinical effects of modulating cortical excitability through non-invasive brain stimulation in treating sleep disorders. In this study, we critically reviewed clinical studies using non-invasive brain stimulation, particularly transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), for treatment of sleep disorders. Previous studies have reported inconsistent therapeutic effects of TMS and tDCS for various kinds of sleep disorders. Specifically, low-frequency repetitive TMS (rTMS) and cathodal tDCS, both of which exert an inhibitory effect on cortical excitability, have shown inconsistent therapeutic effects for insomnia. On the other hand, high-frequency rTMS and anodal tDCS, both of which facilitate cortical excitability, have improved the symptoms of hypersomnia. In studies of restless legs syndrome, high-frequency rTMS and anodal tDCS induced inconsistent therapeutic effects. Single TMS and rTMS have shown differential therapeutic effects for obstructive sleep apnea. These inconsistent findings indicate that the distinctive characteristics of each non-invasive brain stimulation method and specific pathophysiological mechanisms underlying particular sleep disorders should be considered in an integrated manner for treatment of various sleep disorders. Future studies are needed to provide optimized TMS and tDCS protocols for each sleep disorder, considering distinctive effects of non-invasive brain stimulation and pathophysiology of each sleep disorder.

The Effect of Hormonal Changes During the Menstrual Cycle on the Brain: Focusing on Structural and Functional Neuroimaging Studies / 생물치료정신의학

It is well known that sex hormones are potential modulators of brain functions and women experience dynamic hormonal changes during the menstrual cycle. Previous animal studies have reported that the variations in sex hormones over the menstrual cycle may affect cognitive function, emotion, and behavior by altering structures and functional connectivity of the brain. Considering the prevalence of certain neuropsychiatric disorders such as mood and anxiety disorders is relatively high in women, as compared with men, fluctuations of sex hormones over the menstrual cycle may influence the human brain and potentially underlie sex differences in clinical features of several neuropsychiatric disorders. There is, however, little evidence regarding the exact mechanisms underlying the effects of sex hormones on the human brain. In this review, we focused on studies to examine structural and functional changes over the menstrual cycles in women and aimed to provide an up-to-date overview of neuroimaging studies regarding the effects of sex hormonal fluctuations on the brain and behaviors.

Brain Metabolite Changes in Insomnia and Obstructive Sleep Apnea / 수면정신생리

Sleep is essential to brain function and mental health. Insomnia and obstructive sleep apnea (OSA) are the two most common sleep disorders, and are major public health concerns. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive method of quantifying neurometabolite concentrations. Therefore, 1H-MRS studies on individuals with sleep disorders may enhance our understanding of the pathophysiology of these disorders. In this article, we reviewed 1H-MRS studies in insomnia and OSA that reported changes in neurometabolite concentrations. Previous studies have consistently reported insomnia-related reductions in γ-aminobutyric acid (GABA) levels in the frontal and occipital regions, which suggest that changes in GABA are important to the etiology of insomnia. These results may support the hyperarousal theory that insomnia is associated with increased cognitive and physiological arousal. In addition, the severity of insomnia was associated with low glutamate and glutamine levels. Previous studies of OSA have consistently reported reduced N-acetylaspartate (NAA) levels in the frontal, parietooccipital, and temporal regions. In addition, OSA was associated with increased myo-inositol levels. These results may provide evidence that intermittent hypoxia induced by OSA may result in neuronal damage in the brain, which can be related to neurocognitive dysfunction in patients with OSA. The current review summarizes findings related to neurochemical changes in insomnia and OSA. Future well-designed studies using 1H-MRS have the potential to enhance our understanding of the pathophysiology of sleep disorders including insomnia and OSA.

The Effect of Hormonal Changes During the Menstrual Cycle on the Brain: Focusing on Structural and Functional Neuroimaging Studies / 생물치료정신의학

It is well known that sex hormones are potential modulators of brain functions and women experience dynamic hormonal changes during the menstrual cycle. Previous animal studies have reported that the variations in sex hormones over the menstrual cycle may affect cognitive function, emotion, and behavior by altering structures and functional connectivity of the brain. Considering the prevalence of certain neuropsychiatric disorders such as mood and anxiety disorders is relatively high in women, as compared with men, fluctuations of sex hormones over the menstrual cycle may influence the human brain and potentially underlie sex differences in clinical features of several neuropsychiatric disorders. There is, however, little evidence regarding the exact mechanisms underlying the effects of sex hormones on the human brain. In this review, we focused on studies to examine structural and functional changes over the menstrual cycles in women and aimed to provide an up-to-date overview of neuroimaging studies regarding the effects of sex hormonal fluctuations on the brain and behaviors.

Brain Metabolite Changes in Insomnia and Obstructive Sleep Apnea / 수면정신생리

Sleep is essential to brain function and mental health. Insomnia and obstructive sleep apnea (OSA) are the two most common sleep disorders, and are major public health concerns. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive method of quantifying neurometabolite concentrations. Therefore, 1H-MRS studies on individuals with sleep disorders may enhance our understanding of the pathophysiology of these disorders. In this article, we reviewed 1H-MRS studies in insomnia and OSA that reported changes in neurometabolite concentrations. Previous studies have consistently reported insomnia-related reductions in γ-aminobutyric acid (GABA) levels in the frontal and occipital regions, which suggest that changes in GABA are important to the etiology of insomnia. These results may support the hyperarousal theory that insomnia is associated with increased cognitive and physiological arousal. In addition, the severity of insomnia was associated with low glutamate and glutamine levels. Previous studies of OSA have consistently reported reduced N-acetylaspartate (NAA) levels in the frontal, parietooccipital, and temporal regions. In addition, OSA was associated with increased myo-inositol levels. These results may provide evidence that intermittent hypoxia induced by OSA may result in neuronal damage in the brain, which can be related to neurocognitive dysfunction in patients with OSA. The current review summarizes findings related to neurochemical changes in insomnia and OSA. Future well-designed studies using 1H-MRS have the potential to enhance our understanding of the pathophysiology of sleep disorders including insomnia and OSA.

Cognitive Enhancement in Neurological and Psychiatric Disorders Using Transcranial Magnetic Stimulation (TMS): A Review of Modalities, Potential Mechanisms and Future Implications

Cognitive enhancement refers to the improvement of cognitive function related to deficits that occurred as part of a certain illness. However, the term cognitive enhancement does not yet have a definitive meaning, and its connotations often vary depending on the research of interest. Recently, research interests are growing towards enhancing human cognition beyond what has traditionally been considered necessary using various brain devices. The phenomenon of exceeding the cognitive abilities of individuals who are already functional has also introduced new terminologies as means to classify between cognitive enhancing procedures that are part of treatment versus simply supplementary. Of the many devices used to attain cognitive enhancement, transcranial magnetic stimulation (TMS) is a unique neurostimulatory device that has demonstrated significant improvements in various cognitive domains including memory and cognitive processing skills. While many studies have supported the safety and efficacy of TMS in treatment, there has yet to be an optimization in parameter for TMS that is catered to a certain target group. The current paper aims to review with perspective the many studies that have used TMS for the purpose of cognitive enhancement and provide further insight on the development of an optimal stimulation parameter. The paper reviews 41 peer-reviewed articles that used TMS for cognitive enhancement, summarizes the findings that were apparent for each distinct parameter, and discusses future directions regarding TMS as an elective tool for healthy individuals while considering some of the ethical perspectives that may be warranted.

Animal Models of Demyelination and ¹H-Magnetic Resonance Spectroscopy

The proton magnetic resonance spectroscopy (¹H-MRS) is a tool used to detect concentrations of brain metabolites such as N-acetyl aspartate, choline, creatine, glutamate, and gamma-amino butyric acid (GABA). It has been widely used because it does not require additional devices other than the conventional magnetic resonance scanner and coils. Demyelination, or the neuronal damage due to loss of myelin sheath, is one of the common pathologic processes in many diseases including multiple sclerosis, leukodystrophy, encephalomyelitis, and other forms of autoimmune diseases. Rodent models mimicking human demyelinating diseases have been induced by using virus (e.g., Theiler's murine encephalomyelitis virus) or toxins (e.g., cuprizon or lysophosphatidyl choline). This review is an overview of the MRS findings on brain metabolites in demyelination with a specific focus on rodent models.

Reliability and Validity of the Korean Version of the Post-Traumatic Stress Disorder Checklist in Public Firefighters and Rescue Workers

OBJECTIVES: Firefighters and rescue workers are likely to be exposed to a variety of traumatic events; as such, they are vulnerable to the risk of post-traumatic stress disorder (PTSD). The psychometric properties of the Korean version of the PTSD Checklist (PCL), a widely used self-report screening tool for PTSD, were assessed in South Korean firefighters and rescue workers. METHODS: Data were collected via self-report questionnaires and semi-structured clinical interviews administered to 221 firefighters. Internal consistency, item-total correlation, one-week test-retest reliability, convergent validity, and divergent validity were examined. Content validity of the PCL was evaluated using factor analysis and receiver operating characteristic (ROC) analyses were used to estimate the optimal cutoff point and area under the curve. RESULTS: The PCL demonstrated excellent internal consistency (alpha = 0.97), item-total correlation (r = 0.72-0.88), test-retest reliability (r = 0.95), and convergent and divergent validity. The total score of PCL was positively correlated with the number of traumatic events experienced (p < 0.001). Factor analysis revealed two theoretically congruent factors: re-experience/avoidance and numbing/hyperarousal. The optimal cutoff was 45 and the area under the ROC curve was 0.97. CONCLUSIONS: The Korean version of the PCL may be a useful PTSD screening instrument for firefighters and rescue workers, further maximizing opportunities for accurate PTSD diagnosis and treatment.

Molecular Neuroimaging in Posttraumatic Stress Disorder

Over the past decade, an increasing number of neuroimaging studies have provided insight into the neurobiological mechanisms of posttraumatic stress disorder (PSTD). In particular, molecular neuroimaging techniques have been employed in examining metabolic and neurochemical processes in PTSD. This article reviews molecular neuroimaging studies in PTSD and focuses on findings using three imaging modalities including positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance spectroscopy (MRS). Although there were some inconsistences in the findings, patients with PTSD showed altered cerebral metabolism and perfusion, receptor bindings, and metabolite profiles in the limbic regions, medial prefrontal cortex, and temporal cortex. Studies that have investigated brain correlates of treatment response are also reviewed. Lastly, the limitations of the molecular neuroimaging studies and potential future research directions are discussed.

Prefrontal Cortical Thickness Deficit in Detoxified Alcohol-dependent Patients

Alcohol dependence is a serious disorder that can be related with a number of potential health-related and social consequences. Cortical thickness measurements would provide important information on the cortical structural alterations in patients with alcohol dependence. Twenty-one patients with alcohol dependence and 22 healthy comparison subjects have been recruited and underwent high-resolution brain magnetic resonance (MR) imaging and clinical assessments. T1-weighted MR images were analyzed using the cortical thickness analysis program. Significantly thinner cortical thickness in patients with alcohol dependence than healthy comparison subjects was noted in the left superior frontal cortical region, correcting for multiple comparisons and adjusting with age and hemispheric average cortical thickness. There was a significant association between thickness in the cluster of the left superior frontal cortex and the duration of alcohol use. The prefrontal cortical region may particularly be vulnerable to chronic alcohol exposure. It is also possible that the pre-existing deficit in this region may have rendered individuals more susceptible to alcohol dependence.

Strategies for Clinical Application of Neuroscience Findings

Psychiatry has progressed with neurobiological basis, providing individually tailored treatment, preventing mental illness, and managing public mental health. Foundational knowledge that may contribute to the development of psychiatry and neuroscience has been attained through continual national and international investment in research. However, this knowledge obtained from neurobiological research is not being applied to clinical practice proactively. This may be due to a lack of support for translational research connecting neuroscience with clinical practice, and a lack of development and availability of educational programs for clinical psychiatrists. To solve these problems, it is essential to support translational research conducted by clinicians and to establish an appropriate reward system. Considering the direction of progress in psychiatry and the demand from clinicians, appropriate investment in research and education programs that provide neurobiological knowledge applicable to clinical practice is required. Researchers and educators must also communicate and collaborate to deliver neurobiological findings effectively.

Effects of the Combination Herbal Extract on Working Memory and White Matter Integrity in Healthy Individuals with Subjective Memory Complaints : A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

OBJECTIVES: The combination extract of four kinds of herbs, Gastrodia elata, Liriope platyphylla, Dimocarpus longan, and Salvia miltiorrhiza, has shown to have memory improving effects in mice. The aim of this study was to investigate the efficacy and safety of the herbal mixture for improving working memory as well as microstructural changes in white matter integrity in individuals with subjective memory complaints. METHODS: Seventy-five individuals with subjective memory complaints were assigned to receive either placebo (n = 15) or herbal mixture (low-dose group, n = 30 and high-dose group, n = 30) supplementation in an 8-week, randomized, double-blind, placebo-controlled clinical trial. Changes in working memory performance and fractional anisotropy (FA) values reflecting white matter integrity from baseline to 8-week endpoint were assessed. RESULTS: The herbal mixture group showed an increase in working memory performance compared to the placebo group (p for interaction = 0.001). In addition, the herbal mixture group showed an increase in FA values in the temporo-parietal regions (corrected p < 0.05), which are crucially involved in working memory function and are among the most affected regions in patients with cognitive impairments. CONCLUSIONS: Findings from this study indicate that the herbal mixture may be a promising therapeutic option for individuals with subjective memory complaints.

Peripheral Biomarker Candidates of Posttraumatic Stress Disorder

There is high variability in the manifestation of physical and mental health problems following exposure to trauma and disaster. Although most people may show a range of acute symptoms in the aftermath of traumatic events, chronic and persistent mental disorders may not be developed in all individuals who were exposed to traumatic events. The most common long-term pathological consequence after trauma exposure is posttraumatic stress disorder (PTSD). However, comorbid conditions including depression, anxiety disorder, substance use-related problems, and a variety of other symptoms may frequently be observed in individuals with trauma exposure. Post-traumatic syndrome (PTS) is defined collectively as vast psychosocial problems that could be experienced in response to traumatic events. It is important to predict who will continue to suffer from physical and mental health problems and who will recover following trauma exposure. However, given the heterogeneity and variability in symptom manifestations, it is difficult to find identify biomarkers which predict the development of PTSD. In this review, we will summarize the results of recent studies with regard to putative biomarkers of PTSD and suggest future research directions for biomarker discovery for PTSD.

The Role of Oxidative Stress in Neurodegenerative Diseases

Oxidative stress is induced by an imbalanced redox states, involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system. The brain is one of organs especially vulnerable to the effects of ROS because of its high oxygen demand and its abundance of peroxidation-susceptible lipid cells. Previous studies have demonstrated that oxidative stress plays a central role in a common pathophysiology of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Antioxidant therapy has been suggested for the prevention and treatment of neurodegenerative diseases, although the results with regard to their efficacy of treating neurodegenerative disease have been inconsistent. In this review, we will discuss the role of oxidative stress in the pathophysiology of neurodegenerative diseases and in vivo measurement of an index of damage by oxidative stress. Moreover, the present knowledge on antioxidant in the treatment of neurodegenerative diseases and future directions will be outlined.