Fronto-limbic System Research Articles

Role of fronto-limbic circuit in neuropsychiatric symptoms of dementia: clinical evidence from an exploratory study.

Neuropsychiatric symptoms (NPSs) are a distressful aspect of dementia and the knowledge of structural correlates of NPSs is limited. We aimed to identify associations of fronto-limbic circuit with specific NPSs in patients with various types of cognitive impairment. Of 84 participants, 27 were diagnosed with mild cognitive impairment (MCI), 41 with Alzheimer's disease (AD) dementia and 16 with non-AD dementia. In all patients we assessed regional brain morphometry using a region of interest (ROI)-based analysis. The mean cortical thickness (CT) of 20 cortical regions and the volume (V) of 4 subcortical areas of the fronto-limbic system were extracted. NPSs were rated with the Neuropsychiatric Inventory (NPI). We used multiple linear regression models adjusted for age and disease duration to identify significant associations between scores of NPI sub-domains and MRI measures of brain morphometry. All significant associations found were negative, except those between irritability and the fronto-opercular regions in MCI patients (corresponding to a 40-50% increase in CT) and between delusions and hippocampus and anterior cingulate gyrus (with a 40-60% increase). Apathy showed predominant involvement of the inferior frontal regions in AD group (a 30% decrease in CT) and of the cingulate cortex in non-AD group (a 50-60% decrease in CT). Anxiety correlated in MCI patients with the cingulate gyrus and caudate, with a CT and V decrease of about 40%, while hallucinations were associated with left enthorinal gyrus and right amygdala and temporal pole. Agitation showed associations in the AD group with the frontal regions and the temporal pole, corresponding to a 30-40% decrease in CT. Euphoria, disinhibition and eating abnormalities were associated in the MCI group with the entorhinal, para-hippocampal and fusiform gyri, the temporal pole and the amygdala (with a 40-70% decrease in CT and V). Finally, aberrant motor behavior reported a significant association with frontal and cingulate regions with a 50% decrease in CT. Our findings indicate that specific NPSs are associated with the structural involvement of the fronto-limbic circuit across different types of neurocognitive disorders. Factors, such as age and disease duration, can partly account for the variability of the associations observed.

Potential correlations between asymmetric disruption of functional connectivity and metabolism in major depressive disorder

ObjectivePrevious research has suggested a connection between major depressive disorder (MDD) and certain comorbidities, including gastrointestinal issues, thyroid dysfunctions, and glycolipid metabolism abnormalities. However, the relationships between these factors and asymmetrical alterations in functional connectivity (FC) in adults with MDD remain unclear. MethodWe conducted a study on a cohort of 42 MDD patients and 42 healthy controls (HCs). Participants underwent comprehensive clinical assessments, including evaluations of blood lipids and thyroid hormone levels, as well as resting-state functional magnetic resonance imaging (Rs-fMRI) scans. Data analysis involved correlation analysis to compute the parameter of asymmetry (PAS) for the entire brain's functional connectome. We then examined the interrelationships between abnormal PAS regions in the brain, thyroid hormone levels, and blood lipid levels. ResultsThe third-generation ultra-sensitive thyroid stimulating hormone (TSH3UL) level was found to be significantly lower in MDD patients compared to HCs. The PAS score of the left inferior frontal gyrus (IFG) decreased, while the bilateral posterior cingulate cortex (Bi-PCC) PAS increased in MDD patients relative to HCs. Notably, the PAS score of the left IFG negatively correlated with both TSH and total cholesterol (CHOL) levels. However, these correlations lose significance after the Bonferroni correction. ConclusionMDD patients demonstrated abnormal asymmetry in resting-state FC (Rs-FC) within the fronto-limbic system, which may be associated with CHOL and thyroid hormone levels.

Stimulating Reflections on This Issue

Back to table of contents Next article EditorialFull AccessStimulating Reflections on This IssueDanielle W. Lowe, M.D., Ph.D.Danielle W. LoweSearch for more papers by this author, M.D., Ph.D.Published Online:1 Mar 2023https://doi.org/10.1176/appi.ajp-rj.2023.180301AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Sometimes a natural theme occurs in an issue of the American Journal of Psychiatry Residents’ Journal (AJP-RJ), and it would be remiss not to reflect on these articles as a group. The issue starts with a literature review of repetitive transcranial magnetic stimulation (rTMS) as a treatment for anorexia nervosa by Jae H. Kim, B.S., and colleagues (1). Although the efficacy data are limited in both number of trials and length of follow up, the possibility of integrating rTMS into a larger multidisciplinary treatment program to help reduce maladaptive processes in the frontolimbic system is appealing. This review is followed by two History of Psychiatry articles that explore the development and science of rTMS. Dallas Hamlin, M.D., and John Garman, M.D., review the roots of neurostimulation by intertwining the discoveries of electricity and magnetism within the field of psychiatry (2). Alexander Levit, M.D., Ph.D., builds on this foundation, discussing some of the technical details of current and emerging protocols (3). Together, these articles help integrate the reader’s understanding of the fundamentals and potential future directions of rTMS, and I hope you enjoy reading them, as I have.It is also exciting that this issue of the AJP-RJ is being released just a few days before the conclusion of our third virtual residency and fellowship match cycles. I encourage you to read Chris Wang, M.D., and colleagues’ discussion of the limitations and benefits of a virtual match from the perspective of having both types of interviews at different stages of professional training (4). Continued dialogue about how to balance equity and affordability while having a meaningful interview experience is critical. We know even less about the effects of the virtual match on well-being and burnout throughout training. Trainee burnout is not a new topic, and the Accreditation Council for Graduate Medical Education common program requirements include the assessment of and support for well-being (5, 6). However, with only two classes of virtually matched trainees matriculated to date, the longer-term effects of virtual interviews on program satisfaction and burnout are yet to be fully realized. How do virtual interviews contribute to the sense of lack of control during training? What effects did in-person interview dinners and applicant interactions have on trainees in the program? What additional burdens do virtual interviews have on trainees? The authors concluded that a curated group of trainees and faculty could provide enough information about an institution and community’s culture for the interviewee’s match list—but how virtual interviews change the larger residency and fellowship experience remains relatively unknown.Dr. Lowe is a fifth-year child and adolescent psychiatry fellow at the University of North Carolina, Chapel Hill. She is also an American Psychiatric Association Foundation Child and Adolescent Psychiatry fellow (2021–2023) and editor-in-chief of the American Journal of Psychiatry Residents’ Journal (2022–2023).

Resting-state functional connectivity patterns associated with childhood maltreatment in a large bicentric cohort of adults with and without major depression.

Childhood maltreatment (CM) represents a potent risk factor for major depressive disorder (MDD), including poorer treatment response. Altered resting-state connectivity in the fronto-limbic system has been reported in maltreated individuals. However, previous results in smaller samples differ largely regarding localization and direction of effects. We included healthy and depressed samples [n = 624 participants with MDD; n = 701 healthy control (HC) participants] that underwent resting-state functional MRI measurements and provided retrospective self-reports of maltreatment using the Childhood Trauma Questionnaire. A-priori defined regions of interest [ROI; amygdala, hippocampus, anterior cingulate cortex (ACC)] were used to calculate seed-to-voxel connectivities. No significant associations between maltreatment and resting-state connectivity of any ROI were found across MDD and HC participants and no interaction effect with diagnosis became significant. Investigating MDD patients only yielded maltreatment-associated increased connectivity between the amygdala and dorsolateral frontal areas [pFDR < 0.001; η2partial = 0.050; 95%-CI (0.023-0.085)]. This effect was robust across various sensitivity analyses and was associated with concurrent and previous symptom severity. Particularly strong amygdala-frontal associations with maltreatment were observed in acutely depressed individuals [n = 264; pFDR < 0.001; η2partial = 0.091; 95%-CI (0.038-0.166)). Weaker evidence - not surviving correction for multiple ROI analyses - was found for altered supracallosal ACC connectivity in HC individuals associated with maltreatment. The majority of previous resting-state connectivity correlates of CM could not be replicated in this large-scale study. The strongest evidence was found for clinically relevant maltreatment associations with altered adult amygdala-dorsolateral frontal connectivity in depression. Future studies should explore the relevance of this pathway for a maltreated subgroup of MDD patients.

Discriminating Suicide Attempters and Predicting Suicide Risk Using Altered Frontolimbic Resting-State Functional Connectivity in Patients With Bipolar II Disorder.

Bipolar II disorder (BD-II) major depression episode is highly associated with suicidality, and objective neural biomarkers could be key elements to assist in early prevention and intervention. This study aimed to integrate altered brain functionality in the frontolimbic system and machine learning techniques to classify suicidal BD-II patients and predict suicidality risk at the individual level. A cohort of 169 participants were enrolled, including 43 BD-II depression patients with at least one suicide attempt during a current depressive episode (SA), 62 BD-II depression patients without a history of attempted suicide (NSA), and 64 demographically matched healthy controls (HCs). We compared resting-state functional connectivity (rsFC) in the frontolimbic system among the three groups and explored the correlation between abnormal rsFCs and the level of suicide risk (assessed using the Nurses' Global Assessment of Suicide Risk, NGASR) in SA patients. Then, we applied support vector machines (SVMs) to classify SA vs. NSA in BD-II patients and predicted the risk of suicidality. SA patients showed significantly decreased frontolimbic rsFCs compared to NSA patients. The left amygdala-right middle frontal gyrus (orbital part) rsFC was negatively correlated with NGASR in the SA group, but not the severity of depressive or anxiety symptoms. Using frontolimbic rsFCs as features, the SVMs obtained an overall 84% classification accuracy in distinguishing SA and NSA. A significant correlation was observed between the SVMs-predicted NGASR and clinical assessed NGASR (r = 0.51, p = 0.001). Our results demonstrated that decreased rsFCs in the frontolimbic system might be critical objective features of suicidality in BD-II patients, and could be useful for objective prediction of suicidality risk in individuals.

Altered resting-state fMRI signals and network topological properties of bipolar depression patients with anxiety symptoms

BackgroundThis study aims to explore the changes in functional neuroimaging in bipolar depression patients with anxiety symptoms (BDP-A). MethodsForty-five BDP-A patients, 22 bipolar depression patients without anxiety symptoms (BDP-NA), and 48 healthy controls (HC) were finally involved. The low-frequency oscillation characteristics, functional connectivity (FC), and network properties among the three groups of participants were analyzed. ResultsCompared with the BDP-NA group, BDP-A patients exhibited significantly decreased amplitude of low-frequency fluctuation (ALFF) in the left middle frontal gyrus (MFG), superior occipital gyrus, and inferior parietal, but supramarginal and angular gyri (IPL). Enhanced FC from left IPL to middle temporal gyrus, from left precentral gyrus (PreCG) to bilateral angular gyri, medial superior frontal gyrus, and left superior frontal gyrus (SFG)/MFG were also revealed. Compared with HC, the BDP-A group showed remarkably increased ALFF in the left MFG/PreCG, right superior parietal gyrus, while decreased ALFF in the left inferior frontal gyrus, opercular part, and SFG. In addition, higher regional homogeneity in the left MFG/PreCG was found. LimitationsThe limitations are as follows: (1) relatively small sample size; (2) not all the patients were drug-naive; (3) lack of pure anxiety disorder patients as a controlled group; (4) mental health conditions of HC were not systemic evaluated. ConclusionsBDP-A patients showed significant differences in resting-state fMRI properties when compared with BDP-NA or HC group. These results may infer the dysfunction of the dorsal attention network, the default network, and the fronto-limbic system as well as disrupted brain network efficiency in BDP-A patients.

Altered gray matter volume and structural co-variance in adolescents with social anxiety disorder: evidence for a delayed and unsynchronized development of the fronto-limbic system.

Social anxiety disorder (SAD) is a prevalent mental disorder diagnosed in childhood and adolescence. Theories regarding brain development and SAD suggest a close link between neurodevelopmental dysfunction at the adolescent juncture and SAD, but direct evidence is rare. This study aims to examine brain structural abnormalities in adolescents with SAD. High-resolution T1-weighted images were obtained from 31 adolescents with SAD (15-17 years) and 42 matching healthy controls (HC). We evaluated symptom severity with the Social Anxiety Scale for Children (SASC) and the Screen for Child Anxiety Related Emotional Disorders (SCARED). We used voxel-based morphometry analysis to detect regional gray matter volume abnormalities and structural co-variance analysis to investigate inter-regional coordination patterns. We found significantly higher gray matter volume in the orbitofrontal cortex (OFC) and the insula in adolescents with SAD compared to HC. We also observed significant co-variance of the gray matter volume between the OFC and amygdala, and the OFC and insula in HC, but these co-variance relationships diminished in SAD. These findings provide the first evidence that the brain structural deficits in adolescents with SAD are not only in the core regions of the fronto-limbic system, but also represented by the diminished coordination in the development of these regions. The delayed and unsynchronized development pattern of the fronto-limbic system supports SAD as an adolescent-sensitive developmental mental disorder.

Topological changes in white matter connectivity network in patients with Parkinson's disease and depression.

Depression is the most common non-motor symptom accompanying Parkinson's disease (PD) with high prevalence but unclear pathophysiological mechanism. Relatively little is known about the topological patterns of white matter structural networks in depressed patients with PD. In this study, we used diffusion-tensor imaging (DTI) and graph theory approaches to explore the brain structural connectome in non-depressed patients with PD (n = 47), depressed patients with PD (n = 20) and healthy controls (n = 46). All three groups exhibited small-world topology. Compared with healthy controls, non-depressed patients with PD and depressed patients with PD showed a significant reduction of network efficiency in the cortico-subcortical circuits. Moreover, depressed patients with PD exhibited higher network efficiency in fronto-limbic system, compared to non-depressed patients with PD. To sum up, our data indicated a disrupted integrity in the large-scale brain systems in depressed patients with PD patients. The structural connectome provided a basis for functional alterations in depressed patients with PD that may advance our current understanding of pathophysiological mechanism underlying Parkinson's disease.

Brain networks underlying aesthetic appreciation as modulated by interaction of the spectral and temporal organisations of music

Music is organised both spectrally and temporally, determining musical structures such as musical scale, harmony, and sequential rules in chord progressions. A number of human neuroimaging studies investigated neural processes associated with emotional responses to music investigating the influence of musical valence (pleasantness/unpleasantness) comparing the response to music and unpleasantly manipulated counterparts where harmony and sequential rules were varied. Interactions between the previously applied alterations to harmony and sequential rules of the music in terms of emotional experience and corresponding neural activities have not been systematically studied although such interactions are at the core of how music affects the listener. The current study investigates the interaction between such alterations in harmony and sequential rules by using data sets from two functional magnetic resonance imaging (fMRI) experiments. While replicating the previous findings, we found a significant interaction between the spectral and temporal alterations in the fronto-limbic system, including the ventromedial prefrontal cortex (vmPFC), nucleus accumbens, caudate nucleus, and putamen. We further revealed that the functional connectivity between the vmPFC and the right inferior frontal gyrus (IFG) was reduced when listening to excerpts with alterations in both domains compared to the original music. As it has been suggested that the vmPFC operates as a pivotal point that mediates between the limbic system and the frontal cortex in reward-related processing, we propose that this fronto-limbic interaction might be related to the involvement of cognitive processes in the emotional appreciation of music.

Current progress in neuroimaging research on treatment resistant depression

Depression is a common psychiatric disorder, and approximately 30% patients with depression do not respond effectively to standard antidepressant medication; this condition is termed treatment resistant depression (TRD) and its neurobiological mechanism remains unclear. Neuroimaging techniques can non-invasively explore changes in brain structure, function and metabolism. These techniques have been applied in neurobiological research of TRD and revealed critical abnormalities in brain structure, function and metabolism in fronto-limbic system. In this paper, we reviewed the latest progress in neuroimaging researches on TRD, providing new insight and imaging evidence for further neurobiological studies of TRD.

Regional grey matter volume reduction in adolescents engaging in non-suicidal self-injury

There is a high prevalence of non-suicidal self-injury (NSSI) amongst adolescents worldwide and therefore an urgency to investigate the underlying mechanisms that may facilitate such behaviours. This study aimed to investigate neurobiological alterations, specifically in regional brain volumes of the frontolimbic system, in adolescents engaging in NSSI in comparison to healthy controls. Regional grey matter volumes were compared between 29 adolescent female patients who presented with incidents of NSSI on ≥5 days within the last 12 months (DSM-5 criteria for NSSI) and 21 healthy age, gender and education matched controls who had never received any psychiatric diagnosis/treatment, or engaged in NSSI. Significant group effects in regional brain volumes were observed in insula, and a suggested change in the anterior cingulate cortex (ACC), while controlling for total segmented volume. Additionally, ACC volume showed a significant association with past suicide attempts, where estimated marginal means showed even smaller ACC volume in adolescents engaging in NSSI with a history of suicide attempt in comparison to those with no history of suicide attempt, including healthy controls. This study provides the first evidence of volumetric changes in adolescents engaging in NSSI and a potential neurobiological link between NSSI and suicide attempt.

Disentangling the Neural Basis of Cognitive Behavioral Therapy in Psychiatric Disorders: A Focus on Depression

Background: Major depressive disorder (MDD) stands among the most frequent psychiatric disorders. Cognitive behavioral therapy (CBT) has been shown to be effective for treating depression, yet its neural mechanisms of action are not well elucidated. The objective of this work is to assess the available neuroimaging studies exploring CBT’s effects in adult patients with MDD. Methods: Computerized databases were consulted till April 2018 and a research was conducted according to PRISMA guidelines in order to identify original research articles published at any time in English and French languages on this topic. Results: Seventeen studies were identified. Only one study was randomized comparing CBT to pharmacological interventions, and none included an effective control. Following CBT, changes occurred in cerebral areas that are part of the fronto-limbic system, namely the cingulate cortex, prefrontal cortex and amygdala-hippocampal complex. However, the pattern of activation and connectivity in these areas varied across the studies. Conclusion: A considerable heterogeneity exists with regard to study design, adapted CBT type and intensity, and employed neuroimaging paradigms, all of which may partly explain the difference in studies’ outcomes. The lack of randomization and effective controls in most of them makes it difficult to draw formal conclusion whether the observed effects are CBT mediated or due to spontaneous recovery. Despite the observed inconsistencies and dearth of data, CBT appears to exert its anti-depressant effects mainly by modulating the function of affective and cognitive networks devoted to emotions generation and control, respectively. This concept remains to be validated in large scale randomized controlled trials.

Congenital olfactory impairment is linked to cortical changes in prefrontal and limbic brain regions.

The human sense of smell is closely associated with morphological differences of the fronto-limbic system, specifically the piriform cortex and medial orbitofrontal cortex (mOFC). Still it is unclear whether cortical volume in the core olfactory areas and connected brain regions are shaped differently in individuals who suffer from lifelong olfactory deprivation relative to healthy normosmic individuals. To address this question, we examined if regional variations in gray matter volume were associated with smell ability in seventeen individuals with isolated congenital olfactory impairment (COI) matched with sixteen normosmic controls. All subjects underwent whole-brain magnetic resonance imaging, and voxel-based morphometry was used to estimate regional variations in grey matter volume. The analyses showed that relative to controls, COI subjects had significantly larger grey matter volumes in left middle frontal gyrus and right superior frontal sulcus (SFS). COI subjects with severe olfactory impairment (anosmia) had reduced grey matter volume in the left mOFC and increased volume in right piriform cortex and SFS. Within the COI group olfactory ability, measured with the "Sniffin' Sticks" test, was positively associated with larger grey matter volume in right posterior cingulate and parahippocampal cortices whereas the opposite relationship was observed in controls. Across COI subjects and controls, better olfactory detectionthreshold was associated with smaller volume in right piriform cortex, while olfactory identification was negatively associated with right SFS volume. Our findings suggest that lifelong olfactory deprivation trigger changes in the cortical volume of prefrontal and limbic brain regions previously linked to olfactory memory.

Neural and neuroendocrine predictors of pharmacological treatment response in adolescents with depression: A preliminary study

ObjectiveTypically, about 30 to 50% of adolescents with depression fail to respond to evidence-based treatments, including antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs). Efforts for identifying predictors and moderators of treatment response are needed to begin to address critical questions relevant to personalized care in adolescent depression. In this pilot study, we aim to identify biological predictors of response to antidepressant treatment. MethodWe used a multiple levels of analysis approach to evaluate threat system functioning (fronto-limbic system and the associated hormonal cascade) to determine if key biological indexes at baseline could predict improvement in depressive symptoms after eight weeks of antidepressant treatment in adolescents with depression. ResultsNeural predictors of favorable treatment response included lower amygdala connectivity with left supplementary motor area and with right precentral gyrus, and greater amygdala connectivity with right central opercular cortex and Heschl's gyrus connectivity during rest. During an emotion task, neural predictors of treatment response were greater activation of the bilateral anterior cingulate cortex and left medial frontal gyrus. Additionally, different patterns of salivary cortisol obtained in the context of a modified Trier Social Stress Test were associated with those whose depressive symptoms remitted as compared to those whose symptoms persisted. ConclusionsThis approach shows significant promise for identifying predictors of treatment response in adolescents with depression. Future work is needed that incorporates sufficiently powered, randomized control trials to provide the basis by which both predictors and moderators of treatment response are identified. The hope is that this work will inform the development of methods that can guide clinician decision-making in assigning beneficial treatments for adolescents who are suffering from depression.

New Insights into How Serotonin Selective Reuptake Inhibitors Shape the Developing Brain.

Development passes through sensitive periods, during which plasticity allows for genetic and environmental factors to exert indelible influence on the maturation of the organism. In the context of central nervous system (CNS) development, such sensitive periods shape the formation of neuro-circuits that mediate, regulate, and control behavior. This general mechanism allows for development to be guided by both the genetic blueprint, as well as the environmental context. While allowing for adaptation, such sensitive periods are also windows of vulnerability during which external and internal factors can confer risk to brain disorders by derailing adaptive developmental programs. Our group has been particularly interested in developmental periods that are sensitive to serotonin (5-HT) signaling, and impact behavior and cognition relevant to psychiatry. Specifically, we review a 5-HT-sensitive period that impacts fronto-limbic system development, resulting in cognitive, anxiety, and depression-related behaviors. We discuss preclinical data to establish biological plausibility and mechanistic insights. We also summarize epidemiological findings that underscore the potential public health implications resulting from the current practice of prescribing 5-HT reuptake inhibiting antidepressants during pregnancy. These medications enter the fetal circulation, likely perturb 5-HT signaling in the brain, and may be affecting circuit maturation in ways that parallel our findings in the developing rodent brain. More research is needed to better disambiguate the dual effects of maternal symptoms on fetal and child development from the effects of 5-HT reuptake inhibitors on clinical outcomes in the offspring. Birth Defects Research 109:924-932, 2017. © 2017 Wiley Periodicals, Inc.

Alterations in cognitive and emotional brain networks related to depression

It is essential for social interactions if one can process the perceived external world with appropriate cognitive control and well-regulated emotion. However, compared with healthy individuals, patients with major depression disorder (MDD) usually exhibit compromised cognitive and enhanced emotional processes, respectively; and these behavioral changes have been shown to be associated with alterations in functional brain networks. Recent advances of MDD research have been increasingly involving functional magnetic resonance imaging (fMRI) and focusing on brain networks of cognition and emotion, as well as the interaction of these two networks. While inconsistencies and debates noted, the present paper attempts to review and provide a summarized finding for these recent fMRI studies. Converging results have shown that MDD is associated with significant alterations in the fronto-limbic system. Specifically, compared with healthy controls, individuals with MDD usually show hyperactivation to negative facial stimuli in the amygdala, reflecting increased withdrawal, the core syndrome of depression. Some studies have also attempted to use hyperactivities of amygdala as the biomarker and reported its predictive value for MDD. Besides amygdala, increased insula response to disgusting faces was also reported in literature, emphasizing the role of disgust in emotional dysregulation. Cognitive abnormalities in depression mainly concern the default mode and executive control networks. In addition to alterations of regional activation in task state, individuals with MDD exhibit increased functional connectivity of the default mode network in resting state, suggesting enhanced self-referential processes. In particular, higher functional connectivity in the anterior default mode network corresponds with higher level of rumination. In the executive control network, many previous studies observed a decreased activation of dorsolateral prefrontal cortex in depression, indicating impaired ability of cognitive control. At the same time, recent research found that transcranial direct current stimulation in the left dorsolateral prefrontal cortex was helpful for working memory enhancement in individuals with MDD. While alterations were reported in the emotional and cognitive networks separately, interactive changes of these 2 modules have also been examined when they are simultaneously probed. Most studies have noted that when challenged with negative emotion, individuals with depression show increased activation in amygdala and decreased activation in dorsolateral prefrontal cortex, indicating a biased processing resource allocation towards the emotional system. Based on the aforementioned fMRI studies of MDD, we suggest that future improvements may consider aspects of (i) matching depressive syndromes for optimized confounding factor control; (ii) incorporating multimodal approaches for both brain imaging and stimulation; as well as (iii) applying neuroimaging together with psychological therapies either for prognosis evaluation or neurofeedback training.

Cognitive dysfunction and underlying neural basis in substance addiction

As one of the most serious public health problems that extract a high toll on individuals and the society as a whole, substance abuse/addiction has attracted much attention from both researchers and the public. According to the DSM-5, substance addiction is a chronically relapsing psychiatric disorder that has been characterized by compulsion to seek and use drugs, loss of control in limiting intake despite serious negative consequences. However, more than 80% of the individuals with addiction fail to seek treatment, perhaps reflecting their cognitive function impairments. Previous studies have showed that most drugs of abuse exert their reinforcing effects and produce euphoria by inducing dopamine surges in limbic regions, which then have cascading effects on other neurotransmitter systems, leading to characteristic plastic adaptions; significant changes in neural circuits implicated in reward, attention, inhibitory control, decision making and interoception; and cognitive dysfunctions. However, much is still to be learned about the neural mechanisms involved in drugs’ effects on cognitive functions and the vicious cycle of “drug abuse – withdrawal – recovery – relapse”. For a better understanding of the causes of substance addiction and its underlying neural mechanisms, we provide an integrative review of behavioral and neuroimaging studies in substance addiction, introduce a neurobiological model of substance addiction, and finally propose future directions for research and clinical treatment. First, we summarize the research on the cognitive and neural mechanisms involved in substance addiction. (1) Drug-related cues can enhance the activities in the mesocorticolimbic system implicated in reward and drug motivation, which then result in increased attention to the drug-related stimuli. Thus, the neural changes in the frontolimbic system may be a potential neural basis for attentional bias toward drugs in individuals with addiction. (2) The deficit in inhibitory control typically observed in individuals with substance addiction may be due to a dysfunction in their prefrontal cortex-striatothalamic circuitry. (3) These individuals’ poor decision making may be a product of an imbalance between three separate, but interacting, neural systems: the amygdala-striatum (an impulsive system); the prefrontal cortex (a reflective system); and the insula (the interoceptive system). (4) Emerging evidence shows that individuals with drug addiction have interoceptive processing deficits, perhaps due to dysfunctions in brain systems such as the insula and the anterior cingulate cortex. Second, we introduce a neurobiological model of substance addiction that depicts addiction as a result of an imbalance of six interactive circuits (i.e., reward, motivation/drive, memory, executive control, mood, and interoception). These brain circuits interact with one another to attain proper inhibitory control and hence good decision making. During addiction, however, the enhanced activities of six circuits (i.e., reward, motivation, memory, executive control, mood, and interoception) overwhelm the PFC’s inhibitory control and hence lead to craving. Finally, we propose that future studies should (1) use multi-modal imaging techniques, (2) pay attention to comorbidity and clarify the association between addiction and other psychiatric disorders, (3) discover more biomarkers and optimize the diagnostic system using both behavioral and neuroimaging information, and (4) develop brain-based intervention techniques. Such studies should deepen our understanding of substance addiction and provide insights to its treatment.

Functional alterations of fronto-limbic circuit and default mode network systems in first-episode, drug-naïve patients with major depressive disorder: A meta-analysis of resting-state fMRI data

BackgroundThe neurobiological mechanisms of depression are increasingly being explored through resting-state brain imaging studies. However, resting-state fMRI findings have varied, perhaps because of differences between study populations, which included the disorder course and medication use. The aim of our study was to integrate studies of resting-state fMRI and explore the alterations of abnormal brain activity in first-episode, drug-naïve patients with major depressive disorder. MethodsRelevant imaging reports in English were searched, retrieved, selected and subjected to analysis by activation likelihood estimation, a coordinate-based meta-analysis technique (final sample, 31 studies). Coordinates extracted from the original reports were assigned to two categories based on effect directionality. ResultsCompared with healthy controls, the first-episode, medication-naïve major depressive disorder patients showed decreased brain activity in the dorsolateral prefrontal cortex, superior temporal gyrus, posterior precuneus, and posterior cingulate, as well as in visual areas within the occipital lobe, lingual gyrus, and fusiform gyrus, and increased activity in the putamen and anterior precuneus. LimitationsNot every study that has reported relevant data met the inclusion criteria. ConclusionResting-state functional alterations were located mainly in the fronto-limbic system, including the dorsolateral prefrontal cortex and putamen, and in the default mode network, namely the precuneus and superior/middle temporal gyrus. Abnormal functional alterations of the fronto-limbic circuit and default mode network may be characteristic of first-episode, drug-naïve major depressive disorder patients.

Individualized Prediction and Clinical Staging of Bipolar Disorders Using Neuroanatomical Biomarkers

BackgroundNeuroanatomical abnormalities in bipolar disorder (BD) have previously been reported. However, the utility of these abnormalities in distinguishing individual patients with BD from healthy control subjects and stratifying patients based on overall illness burden has not been investigated in a large cohort. MethodsWe examined whether structural neuroimaging scans coupled with a machine learning algorithm are able to distinguish individual patients with BD from healthy control subjects in a large cohort of 256 subjects. Additionally, we investigated the relationship between machine learning–predicted probability scores and clinical characteristics of subjects, such as illness duration and clinical stages. Neuroimaging scans were acquired from 128 patients with BD and 128 healthy control subjects. Gray and white matter density maps were obtained and used to train a relevance vector machine learning algorithm, which was used to distinguish individual patients from healthy control subjects. ResultsThe relevance vector machine algorithm distinguished patients from healthy control subjects with 70.3% accuracy (74.2% specificity, 66.4% sensitivity, χ2p < .005) using white matter density data and 64.9% accuracy (71.1% specificity, 58.6% sensitivity, χ2p < .005) using gray matter density. Multiple brain regions, largely covering the frontolimbic system, were identified as “most relevant” in distinguishing both groups. Patients identified by the algorithm with high certainty (a high probability score) belonged to a subgroup with >10 total lifetime manic episodes including hospitalizations (late-stage BD). ConclusionsThese results indicate the presence of widespread structural brain abnormalities in BD that are associated with higher illness burden, which points to neuroprogression.

A novel analytical brain block tool to enable functional annotation of discriminatory transcript biomarkers among discrete regions of the fronto-limbic circuit in primate brain

Fronto-limbic circuits in the primate brain are responsible for executive function, learning and memory, and emotions, including fear. Consequently, changes in gene expression in cortical and subcortical brain regions housing these circuits are associated with many important psychiatric and neurological disorders. While high quality gene expression profiles can be identified in brains from model organisms, primate brains have unique features such as Brodmann Area 25, which is absent in rodents, yet profoundly important in primates, including humans. The potential insights to be gained from studying the human brain are complicated by the fact that the post-mortem interval (PMI) is variable, and most repositories keep solid tissue in the deep frozen state. Consequently, sampling the important medial and internal regions of these brains is difficult. Here we describe a novel method for obtaining discrete regions from the fronto-limbic circuits of a 4 year old and a 5 year old, male, intact, frozen non-human primate (NHP) brain, for which the PMI is exactly known. The method also preserves high quality RNA, from which we use transcriptional profiling and a new algorithm to identify region-exclusive RNA signatures for Area 25 (NFκB and dopamine receptor signaling), the anterior cingulate cortex (LXR/RXR signaling), the amygdala (semaphorin signaling), and the hippocampus (Ca++ and retinoic acid signaling). The RNA signatures not only reflect function of the different regions, but also include highly expressed RNAs for which function is either poorly understood, or which generate proteins presently lacking annotated functions. We suggest that this new approach will provide a useful strategy for identifying changes in fronto-limbic system biology underlying normal development, aging and disease in the human brain.