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Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications

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• Published: 13 February 2021
• Volume 37 , pages 863–880, ( 2021 )

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• Zezhi Li 1 , 2 ,
• Meihua Ruan 3 ,
• Jun Chen 1 , 5 &
• Yiru Fang   ORCID: orcid.org/0000-0002-8748-9085 1 , 4 , 5  

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A Correction to this article was published on 17 May 2021

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Major depressive disorder (MDD), also referred to as depression, is one of the most common psychiatric disorders with a high economic burden. The etiology of depression is still not clear, but it is generally believed that MDD is a multifactorial disease caused by the interaction of social, psychological, and biological aspects. Therefore, there is no exact pathological theory that can independently explain its pathogenesis, involving genetics, neurobiology, and neuroimaging. At present, there are many treatment measures for patients with depression, including drug therapy, psychotherapy, and neuromodulation technology. In recent years, great progress has been made in the development of new antidepressants, some of which have been applied in the clinic. This article mainly reviews the research progress, pathogenesis, and treatment of MDD.

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Introduction

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Major depressive disorder (MDD) also referred to as depression, is one of the most severe and common psychiatric disorders across the world. It is characterized by persistent sadness, loss of interest or pleasure, low energy, worse appetite and sleep, and even suicide, disrupting daily activities and psychosocial functions. Depression has an extreme global economic burden and has been listed as the third largest cause of disease burden by the World Health Organization since 2008, and is expected to rank the first by 2030 [ 1 , 2 ]. In 2016, the Global Burden of Diseases, Injuries, and Risk Factors Study demonstrated that depression caused 34.1 million of the total years lived with disability (YLDs), ranking as the fifth largest cause of YLD [ 3 ]. Therefore, the research progress and the clinical application of new discoveries or new technologies are imminent. In this review, we mainly discuss the current situation of research, developments in pathogenesis, and the management of depression.

Current Situation of Research on Depression

Analysis of published papers.

In the past decade, the total number of papers on depression published worldwide has increased year by year as shown in Fig. 1 A. Searching the Web of Science database, we found a total of 43,863 papers published in the field of depression from 2009 to 2019 (search strategy: TI = (depression$) or ts = ("major depressive disorder$")) and py = (2009 – 2019), Articles). The top 10 countries that published papers on the topic of depression are shown in Fig. 1 B. Among them, researchers in the USA published the most papers, followed by China. Compared with the USA, the gap in the total number of papers published in China is gradually narrowing (Fig. 1 C), but the quality gap reflected by the index (the total number of citations and the number of citations per paper) is still large, and is lower than the global average (Fig. 1 D). As shown in Fig. 1 E, the hot research topics in depression are as follows: depression management in primary care, interventions to prevent depression, the pathogenesis of depression, comorbidity of depression and other diseases, the risks of depression, neuroimaging studies of depression, and antidepressant treatment.

Analysis of published papers around the world from 2009 to 2019 in depressive disorder. A The total number of papers [from a search of the Web of Science database (search strategy: TI = (depression$) or ts = ("major depressive disorder$")) and py = (2009 – 2019), Articles)]. B The top 10 countries publishing on the topic. C Comparison of papers in China and the USA. D Citations for the top 10 countries and comparison with the global average. E Hot topics.

Analysis of Patented Technology Application

There were 16,228 patent applications in the field of depression between 2009 and 2019, according to the Derwent Innovation Patent database. The annual number and trend of these patents are shown in Fig. 2 A. The top 10 countries applying for patents related to depression are shown in Fig. 2 B. The USA ranks first in the number of depression-related patent applications, followed by China. The largest number of patents related to depression is the development of antidepressants, and drugs for neurodegenerative diseases such as dementia comorbid with depression. The top 10 technological areas of patents related to depression are shown in Fig. 2 C, and the trend in these areas have been stable over the past decade (Fig. 2 D).

Analysis of patented technology applications from 2009 to 2019 in the field of depressive disorder. A Annual numbers and trends of patents (the Derwent Innovation patent database). B The top 10 countries/regions applying for patents. C The top 10 technological areas of patents. D The trend of patent assignees. E Global hot topic areas of patents.

Analysis of technical hotspots based on keyword clustering was conducted from the Derwent Innovation database using the "ThemeScape" tool. This demonstrated that the hot topic areas are as follows (Fig. 2 E): (1) improvement for formulation and the efficiency of hydrobromide, as well as optimization of the dosage; intervention for depression comorbid with AD, diabetes, and others; (3) development of alkyl drugs; (4) development of pharmaceutical acceptable salts as antidepressants; (5) innovation of the preparation of antidepressants; (6) development of novel antidepressants based on neurotransmitters; (7) development of compositions based on nicotinic acetylcholine receptors; and (8) intervention for depression with traditional Chinese medicine.

Analysis of Clinical Trial

There are 6,516 clinical trials in the field of depression in the ClinicalTrials.gov database, and among them, 1,737 valid trials include the ongoing recruitment of subjects, upcoming recruitment of subjects, and ongoing clinical trials. These clinical trials are mainly distributed in the USA (802 trials), Canada (155), China (114), France (93), Germany (66), UK (62), Spain (58), Denmark (41), Sweden (39), and Switzerland (23). The indications for clinical trials include various types of depression, such as minor depression, depression, severe depression, perinatal depression, postpartum depression, and depression comorbid with other psychiatric disorders or physical diseases, such as schizophrenia, epilepsy, stroke, cancer, diabetes, cardiovascular disease, and Parkinson's disease.

Based on the database of the Chinese Clinical Trial Registry website, a total of 143 clinical trials for depression have been carried out in China. According to the type of research, they are mainly interventional and observational studies, as well as a small number of related factor studies, epidemiological studies, and diagnostic trials. The research content involves postpartum, perinatal, senile, and other age groups with clinical diagnosis (imaging diagnosis) and intervention studies (drugs, acupuncture, electrical stimulation, transcranial magnetic stimulation). It also includes intervention studies on depression comorbid with coronary heart disease, diabetes, and heart failure.

New Medicine Development

According to the Cortellis database, 828 antidepressants were under development by the end of 2019, but only 292 of these are effective and active (Fig. 3 A). Large number of them have been discontinued or made no progress, indicating that the development of new drugs in the field of depression is extremely urgent.

New medicine development from 2009 to 2019 in depressive disorder. A Development status of new candidate drugs. B Top target-based actions.

From the perspective of target-based actions, the most common new drugs are NMDA receptor antagonists, followed by 5-HT targets, as well as dopamine receptor agonists, opioid receptor antagonists and agonists, AMPA receptor modulators, glucocorticoid receptor antagonists, NK1 receptor antagonists, and serotonin transporter inhibitors (Fig. 3 B).

Epidemiology of Depression

The prevalence of depression varies greatly across cultures and countries. Previous surveys have demonstrated that the 12-month prevalence of depression was 0.3% in the Czech Republic, 10% in the USA, 4.5% in Mexico, and 5.2% in West Germany, and the lifetime prevalence of depression was 1.0% in the Czech Republic, 16.9% in the USA, 8.3% in Canada, and 9.0% in Chile [ 4 , 5 ]. A recent meta-analysis including 30 Countries showed that lifetime and 12-month prevalence depression were 10.8% and 7.2%, respectively [ 6 ]. In China, the lifetime prevalence of depression ranged from 1.6% to 5.5% [ 7 , 8 , 9 ]. An epidemiological study demonstrated that depression was the most common mood disorder with a life prevalence of 3.4% and a 12-month prevalence of 2.1% in China [ 10 ].

Some studies have also reported the prevalence in specific populations. The National Comorbidity Survey-Adolescent Supplement (NCS-A) survey in the USA showed that the lifetime and 12-month prevalence of depression in adolescents aged 13 to 18 were 11.0% and 7.5%, respectively [ 11 ]. A recent meta-analysis demonstrated that lifetime prevalence and 12-month prevalence were 2.8% and 2.3%, respectively, among the elderly population in China [ 12 ].

Neurobiological Pathogenesis of Depressive Disorder

The early hypothesis of monoamines in the pathophysiology of depression has been accepted by the scientific community. The evidence that monoamine oxidase inhibitors and tricyclic antidepressants promote monoamine neurotransmission supports this theory of depression [ 13 ]. So far, selective serotonin reuptake inhibitors and norepinephrine reuptake inhibitors are still the first-line antidepressants. However, there remain 1/3 to 2/3 of depressed patients who do not respond satisfactorily to initial antidepressant treatment, and even as many as 15%–40% do not respond to several pharmacological medicines [ 14 , 15 ]. Therefore, the underlying pathogenesis of depression is far beyond the simple monoamine mechanism.

Other hypotheses of depression have gradually received increasing attention because of biomarkers for depression and the effects pharmacological treatments, such as the stress-responsive hypothalamic pituitary adrenal (HPA) axis, neuroendocrine systems, the neurotrophic family of growth factors, and neuroinflammation.

Stress-Responsive HPA Axis

Stress is causative or a contributing factor to depression. Particularly, long-term or chronic stress can lead to dysfunction of the HPA axis and promote the secretion of hormones, including cortisol, adrenocorticotropic hormone, corticotropin-releasing hormone, arginine vasopressin, and vasopressin. About 40%–60% of patients with depression display a disturbed HPA axis, including hypercortisolemia, decreased rhythmicity, and elevated cortisol levels [ 16 , 17 ]. Mounting evidence has shown that stress-induced abnormality of the HPA axis is associated with depression and cognitive impairment, which is due to the increased secretion of cortisol and the insufficient inhibition of glucocorticoid receptor regulatory feedback [ 18 , 19 ]. In addition, it has been reported that the increase in cortisol levels is related to the severity of depression, especially in melancholic depression [ 20 , 21 ]. Further, patients with depression whose HPA axis was not normalized after treatment had a worse clinical response and prognosis [ 22 , 23 ]. Despite the above promising insights, unfortunately previous studies have shown that treatments regulating the HPA axis, such as glucocorticoid receptor antagonists, do not attenuate the symptoms of depressed patients [ 24 , 25 ].

Glutamate Signaling Pathway

Glutamate is the main excitatory neurotransmitter released by synapses in the brain; it is involved in synaptic plasticity, cognitive processes, and reward and emotional processes. Stress can induce presynaptic glutamate secretion by neurons and glutamate strongly binds to ionotropic glutamate receptors (iGluRs) including N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) [ 26 ] on the postsynaptic membrane to activate downstream signal pathways [ 27 ]. Accumulating evidence has suggested that the glutamate system is associated with the incidence of depression. Early studies have shown increased levels of glutamate in the peripheral blood, cerebrospinal fluid, and brain of depressed patients [ 28 , 29 ], as well as NMDAR subunit disturbance in the brain [ 30 , 31 ]. Blocking the function of NMDARs has an antidepressant effect and protects hippocampal neurons from morphological abnormalities induced by stress, while antidepressants reduce glutamate secretion and NMDARs [ 32 ]. Most importantly, NMDAR antagonists such as ketamine have been reported to have profound and rapid antidepressant effects on both animal models and the core symptoms of depressive patients [ 33 ]. On the other hand, ketamine can also increase the AMPAR pathway in hippocampal neurons by up-regulating the AMPA glutamate receptor 1 subunit [ 34 ]. Further, the AMPAR pathway may be involved in the mechanism of antidepressant effects. For example, preclinical studies have indicated that AMPAR antagonists might attenuate lithium-induced depressive behavior by increasing the levels of glutamate receptors 1 and 2 in the mouse hippocampus [ 35 ].

Gamma-Aminobutyric Acid (GABA)

Contrary to glutamate, GABA is the main inhibitory neurotransmitter. Although GABA neurons account for only a small proportion compared to glutamate, inhibitory neurotransmission is essential for brain function by balancing excitatory transmission [ 36 ]. Number of studies have shown that patients with depression have neurotransmission or functional defects of GABA [ 37 , 38 ]. Schür et al ., conducted a meta-analysis of magnetic resonance spectroscopy studies, which showed that the brain GABA level in depressive patients was lower than that in healthy controls, but no difference was found in depressive patients in remission [ 39 ]. Several postmortem studies have shown decreased levels of the GABA synthase glutamic acid decarboxylase in the prefrontal cortex of patients with depression [ 40 , 41 ]. It has been suggested that a functional imbalance of the GABA and glutamate systems contributes to the pathophysiology of depression, and activation of the GABA system might induce antidepressant activity, by which GABA A  receptor mediators α2/α3 are considered potential antidepressant candidates [ 42 , 43 ]. Genetic mouse models, such as the GABA A receptor mutant mouse and conditional the Gad1-knockout mouse (GABA in hippocampus and cerebral cortex decreased by 50%) and optogenetic methods have verified that depression-like behavior is induced by changing the level of GABA [ 44 , 45 ].

Neurotrophin Family

The neurotrophin family plays a key role in neuroplasticity and neurogenesis. The neurotrophic hypothesis of depression postulates that a deficit of neurotrophic support leads to neuronal atrophy, the reduction of neurogenesis, and the destruction of glia support, while antidepressants attenuate or reverse these pathophysiological processes [ 46 ]. Among them, the most widely accepted hypothesis involves brain-derived neurotrophic factor (BDNF). This was initially triggered by evidence that stress reduces the BDNF levels in the animal brain, while antidepressants rescue or attenuate this reduction [ 47 , 48 ], and agents involved in the BDNF system have been reported to exert antidepressant-like effects [ 49 , 50 ]. In addition, mounting studies have reported that the BDNF level is decreased in the peripheral blood and at post-mortem in depressive patients, and some have reported that antidepressant treatment normalizes it [ 51 , 52 ]. Furthermore, some evidence also showed that the interaction of BDNF and its receptor gene is associated with treatment-resistant depression [ 15 ].

Recent studies reported that depressed patients have a lower level of the pro-domain of BDNF (BDNF pro-peptide) than controls. This is located presynaptically and promotes long-term depression in the hippocampus, suggesting that it is a promising synaptic regulator [ 53 ].

Neuroinflammation

The immune-inflammation hypothesis has attracted much attention, suggesting that the interactions between inflammatory pathways and neural circuits and neurotransmitters are involved in the pathogenesis and pathophysiological processes of depression. Early evidence found that patients with autoimmune or infectious diseases are more likely to develop depression than the general population [ 54 ]. In addition, individuals without depression may display depressive symptoms after treatment with cytokines or cytokine inducers, while antidepressants relieve these symptoms [ 55 , 56 ]. There is a complex interaction between the peripheral and central immune systems. Previous evidence suggested that peripheral inflammation/infection may spread to the central nervous system in some way and cause a neuroimmune response [ 55 , 57 ]: (1) Some cytokines produced in the peripheral immune response, such as IL-6 and IL-1 β, can leak into the brain through the blood-brain barrier (BBB). (2) Cytokines entering the central nervous system act directly on astrocytes, small stromal cells, and neurons. (3) Some peripheral immune cells can cross the BBB through specific transporters, such as monocytes. (4) Cytokines and chemokines in the circulation activate the central nervous system by regulating the surface receptors of astrocytes and endothelial cells at the BBB. (5) As an intermediary pathway, the immune inflammatory response transmits peripheral danger signals to the center, amplifies the signals, and shows the external phenotype of depressive behavior associated with stress/trauma/infection. (6) Cytokines and chemokines may act directly on neurons, change their plasticity and promote depression-like behavior.

Patients with depression show the core feature of the immune-inflammatory response, that is, increased concentrations of pro-inflammatory cytokines and their receptors, chemokines, and soluble adhesion molecules in peripheral blood and cerebrospinal fluid [ 58 , 59 , 60 ]. Peripheral immune-inflammatory response markers not only change the immune activation state in the brain that affects explicit behavior, but also can be used as an evaluation index or biological index of antidepressant therapy [ 61 , 62 ]. Li et al . showed that the level of TNF-α in patients with depression prior to treatment was higher than that in healthy controls. After treatment with venlafaxine, the level of TNF-α in patients with depression decreased significantly, and the level of TNF-α in the effective group decreased more [ 63 ]. A recent meta-analysis of 1,517 patients found that antidepressants significantly reduced peripheral IL-6, TNF-α, IL-10, and CCL-2, suggesting that antidepressants reduce markers of peripheral inflammatory factors [ 64 ]. Recently, Syed et al . also confirmed that untreated patients with depression had higher levels of inflammatory markers and increased levels of anti-inflammatory cytokines after antidepressant treatment, while increased levels of pro-inflammatory cytokines were found in non-responders [ 62 ]. Clinical studies have also found that anti-inflammatory cytokines, such as monoclonal antibodies and other cytokine inhibitors, may play an antidepressant role by blocking cytokines. The imbalance of pro-inflammatory and anti-inflammatory cytokines may be involved in the pathophysiological process of depression.

In addition, a recent study showed that microglia contribute to neuronal plasticity and neuroimmune interaction that are involved in the pathophysiology of depression [ 65 ]. When activated microglia promote inflammation, especially the excessive production of pro-inflammatory factors and cytotoxins in the central nervous system, depression-like behavior can gradually develop [ 65 , 66 ]. However, microglia change polarization as two types under different inflammatory states, regulating the balance of pro- and anti-inflammatory factors. These two types are M1 and M2 microglia; the former produces large number of pro-inflammatory cytokines after activation, and the latter produces anti-inflammatory cytokines. An imbalance of M1/M2 polarization of microglia may contribute to the pathophysiology of depression [ 67 ].

Microbiome-Gut-Brain Axis

The microbiota-gut-brain axis has recently gained more attention because of its ability to regulate brain activity. Many studies have shown that the microbiota-gut-brain axis plays an important role in regulating mood, behavior, and neuronal transmission in the brain [ 68 , 69 ]. It is well established that comorbidity of depression and gastrointestinal diseases is common [ 70 , 71 ]. Some antidepressants can attenuate the symptoms of patients with irritable bowel syndrome and eating disorders [ 72 ]. It has been reported that gut microbiome alterations are associated with depressive-like behaviors [ 73 , 74 ], and brain function [ 75 ]. Early animal studies have shown that stress can lead to long-term changes in the diversity and composition of intestinal microflora, and is accompanied by depressive behavior [ 76 , 77 ]. Interestingly, some evidence indicates that rodents exhibit depressive behavior after fecal transplants from patients with depression [ 74 ]. On the other hand, some probiotics attenuated depressive-like behavior in animal studies, [ 78 ] and had antidepressant effects on patients with depression in several double-blind, placebo-controlled clinical trials [ 79 , 80 ].

The potential mechanism may be that gut microbiota can interact with the brain through a variety of pathways or systems, including the HPA axis, and the neuroendocrine, autonomic, and neuroimmune systems [ 81 ]. For example, recent evidence demonstrated that gut microbiota can affect the levels of neurotransmitters in the gut and brain, including serotonin, dopamine, noradrenalin, glutamate, and GABA [ 82 ]. In addition, recent studies showed that changes in gut microbiota can also impair the gut barrier and promote higher levels of peripheral inflammatory cytokines [ 83 , 84 ]. Although recent research in this area has made significant progress, more clinical trials are needed to determine whether probiotics have any effect on the treatment of depression and what the potential underlying mechanisms are.

Other Systems and Pathways

There is no doubt that several other systems or pathways are also involved in the pathophysiology of depression, such as oxidant-antioxidant imbalance [ 85 ], mitochondrial dysfunction [ 86 , 87 ], and circadian rhythm-related genes [ 88 ], especially their critical interactions ( e.g. interaction between the HPA and mitochondrial metabolism [ 89 , 90 ], and the reciprocal interaction between oxidative stress and inflammation [ 2 , 85 ]). The pathogenesis of depression is complex and all the hypotheses should be integrated to consider the many interactions between various systems and pathways.

Advances in Various Kinds of Research on Depressive Disorder

Genetic, molecular, and neuroimaging studies continue to increase our understanding of the neurobiological basis of depression. However, it is still not clear to what extent the results of neurobiological studies can help improve the clinical and functional prognosis of patients. Therefore, over the past 10 years, the neurobiological study of depression has become an important measure to understand the pathophysiological mechanism and guide the treatment of depression.

Genetic Studies

Previous twin and adoption studies have indicated that depression has relatively low rate of heritability at 37% [ 91 ]. In addition, environmental factors such as stressful events are also involved in the pathogenesis of depression. Furthermore, complex psychiatric disorders, especially depression, are considered to be polygenic effects that interact with environmental factors [ 13 ]. Therefore, reliable identification of single causative genes for depression has proved to be challenging. The first genome-wide association studies (GWAS) for depression was published in 2009, and included 1,738 patients and 1,802 controls [ 92 , 93 ]. Although many subsequent GWASs have determined susceptible genes in the past decade, the impact of individual genes is so small that few results can be replicated [ 94 , 95 ]. So far, it is widely accepted that specific single genetic mutations may play minor and marginal roles in complex polygenic depression. Another major recognition in GWASs over the past decade is that prevalent candidate genes are usually not associated with depression. Further, the inconsistent results may also be due to the heterogeneity and polygenic nature of genetic and non-genetic risk factors for depression as well as the heterogeneity of depression subtypes [ 95 , 96 ]. Therefore, to date, the quality of research has been improved in two aspects: (1) the sample size has been maximized by combining the data of different evaluation models; and (2) more homogenous subtypes of depression have been selected to reduce phenotypic heterogeneity [ 97 ]. Levinson et al . pointed out that more than 75,000 to 100,000 cases should be considered to detect multiple depression associations [ 95 ]. Subsequently, several recent GWASs with larger sample sizes have been conducted. For example, Okbay et al . identified two loci associated with depression and replicated them in separate depression samples [ 98 ]. Wray et al . also found 44 risk loci associated with depression based on 135,458 cases and 344,901 controls [ 99 ]. A recent GWAS of 807,553 individuals with depression reported that 102 independent variants were associated with depression; these were involved in synaptic structure and neural transmission, and were verified in a further 1,507,153 individuals [ 100 ]. However, even with enough samples, GWASs still face severe challenges. A GWAS only marks the region of the genome and is not directly related to the potential biological function. In addition, a genetic association with the indicative phenotype of depression may only be part of many pathogenic pathways, or due to the indirect influence of intermediate traits in the causal pathway on the final result [ 101 ].

Given the diversity of findings, epigenetic factors are now being investigated. Recent studies indicated that epigenetic mechanisms may be the potential causes of "loss of heritability" in GWASs of depression. Over the past decade, a promising discovery has been that the effects of genetic information can be directly influenced by environment factors, and several specific genes are activated by environmental aspects. This process is described as interactions between genes and the environment, which is identified by the epigenetic mechanism. Environmental stressors cause alterations in gene expression in the brain, which may cause abnormal neuronal plasticity in areas related to the pathogenesis of the disease. Epigenetic events alter the structure of chromatin, thereby regulating gene expression involved in neuronal plasticity, stress behavior, depressive behavior, and antidepressant responses, including DNA methylation, histone acetylation, and the role of non-coding RNA. These new mechanisms of trans-generational transmission of epigenetic markers are considered a supplement to orthodox genetic heredity, providing the possibility for the discovery of new treatments for depression [ 102 , 103 ]. Recent studies imply that life experiences, including stress and enrichment, may affect cellular and molecular signaling pathways in sperm and influence the behavioral and physiological phenotypes of offspring in gender-specific patterns, which may also play an important role in the development of depression [ 103 ].

Brain Imaging and Neuroimaging Studies

Neuroimaging, including magnetic resonance imaging (MRI) and molecular imaging, provides a non-invasive technique for determining the underlying etiology and individualized treatment for depression. MRI can provide important data on brain structure, function, networks, and metabolism in patients with depression; it includes structural MRI (sMRI), functional MRI (fMRI), diffusion tensor imaging, and magnetic resonance spectroscopy.

Previous sMRI studies have found damaged gray matter in depression-associated brain areas, including the frontal lobe, anterior cingulate gyrus, hippocampus, putamen, thalamus, and amygdala. sMRI focuses on the thickness of gray matter and brain morphology [ 104 , 105 ]. A recent meta-analysis of 2,702 elderly patients with depression and 11,165 controls demonstrated that the volumes of the whole brain and hippocampus of patients with depression were lower than those of the control group [ 106 ]. Some evidence also showed that the hippocampal volume in depressive patients was lower than that of controls, and increased after treatment with antidepressants [ 107 ] and electroconvulsive therapy (ECT) [ 108 ], suggesting that the hippocampal volume plays a critical role in the development, treatment response, and clinical prognosis of depression. A recent study also reported that ECT increased the volume of the right hippocampus, amygdala, and putamen in patients with treatment-resistant depression [ 109 ]. In addition, postmortem research supported the MRI study showing that dentate gyrus volume was decreased in drug-naive patients with depression compared to healthy controls, and was potentially reversed by treatment with antidepressants [ 110 ].

Diffusion tensor imaging detects the microstructure of the white matter, which has been reported impaired in patients with depression [ 111 ]. A recent meta-analysis that included first-episode and drug-naïve depressive patients showed that the decrease in fractional anisotropy was negatively associated with illness duration and clinical severity [ 112 ].

fMRI, including resting-state and task-based fMRI, can divide the brain into self-related regions, such as the anterior cingulate cortex, posterior cingulate cortex, medial prefrontal cortex, precuneus, and dorsomedial thalamus. Many previous studies have shown the disturbance of several brain areas and intrinsic neural networks in patients with depression which could be rescued by antidepressants [ 113 , 114 , 115 , 116 ]. Further, some evidence also showed an association between brain network dysfunction and the clinical correlates of patients with depression, including clinical symptoms [ 117 ] and the response to antidepressants [ 118 , 119 ], ECT [ 120 , 121 ], and repetitive transcranial magnetic stimulation [ 122 ].

It is worth noting that brain imaging provides new insights into the large-scale brain circuits that underlie the pathophysiology of depressive disorder. In such studies, large-scale circuits are often referred to as “networks”. There is evidence that a variety of circuits are involved in the mechanisms of depressive disorder, including disruption of the default mode, salience, affective, reward, attention, and cognitive control circuits [ 123 ]. Over the past decade, the study of intra-circuit and inter-circuit connectivity dysfunctions in depression has escalated, in part due to advances in precision imaging and analysis techniques [ 124 ]. Circuit dysfunction is a potential biomarker to guide psychopharmacological treatment. For example, Williams et al . found that hyper-activation of the amygdala is associated with a negative phenotype that can predict the response to antidepressants [ 125 ]. Hou et al . showed that the baseline characteristics of the reward circuit predict early antidepressant responses [ 126 ].

Molecular imaging studies, including single photon emission computed tomography and positron emission tomography, focus on metabolic aspects such as amino-acids, neurotransmitters, glucose, and lipids at the cellular level in patients with depression. A recent meta-analysis examined glucose metabolism and found that glucose uptake dysfunction in different brain regions predicts the treatment response [ 127 ].

The most important and promising studies were conducted by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, which investigated the human brain across 43 countries. The ENIGMA-MDD Working Group was launched in 2012 to detect the structural and functional changes associated with MDD reliably and replicate them in various samples around the world [ 128 ]. So far, the ENIGMA-MDD Working Group has collected data from 4,372 MDD patients and 9,788 healthy controls across 14 countries, including 45 cohorts [ 128 ]. Their findings to date are shown in Table 1 [ 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 ].

Objective Index for Diagnosis of MDD

To date, the clinical diagnosis of depression is subjectively based on interviews according to diagnostic criteria ( e.g. International Classification of Diseases and Diagnostic and Statistical Manual diagnostic systems) and the severity of clinical symptoms are assessed by questionnaires, although patients may experience considerable differences in symptoms and subtypes [ 138 ]. Meanwhile, biomarkers including genetics, epigenetics, peripheral gene and protein expression, and neuroimaging markers may provide a promising supplement for the development of the objective diagnosis of MDD, [ 139 , 140 , 141 ]. However, the development of reliable diagnosis for MDD using biomarkers is still difficult and elusive, and all methods based on a single marker are insufficiently specific and sensitive for clinical use [ 142 ]. Papakostas et al . showed that a multi-assay, serum-based test including nine peripheral biomarkers (soluble tumor necrosis factor alpha receptor type II, resistin, prolactin, myeloperoxidase, epidermal growth factor, BDNF, alpha1 antitrypsin, apolipoprotein CIII, brain-derived neurotrophic factor, and cortisol) yielded a specificity of 81.3% and a sensitivity of 91.7% [ 142 ]. However, the sample size was relatively small and no other studies have yet validated their results. Therefore, further studies are needed to identify biomarker models that integrate all biological variables and clinical features to improve the specificity and sensitivity of diagnosis for MDD.

Management of Depression

The treatment strategies for depression consist of pharmacological treatment and non-pharmacological treatments including psychotherapy, ECT [ 98 ], and transcranial magnetic stimulation. As psychotherapy has been shown to have effects on depression including attenuating depressive symptoms and improving the quality of life [ 143 , 144 ]; several practice guidelines are increasingly recommending psychotherapy as a monotherapy or in combination with antidepressants [ 145 , 146 ].

Current Antidepressant Treatment

Antidepressants approved by the US Food and Drug Administration (FDA) are shown in Table 2 . Due to the relatively limited understanding of the etiology and pathophysiology of depression, almost all the previous antidepressants were discovered by accident a few decades ago. Although most antidepressants are usually safe and effective, there are still some limitations, including delayed efficacy (usually 2 weeks) and side-effects that affect the treatment compliance [ 147 ]. In addition, <50% of all patients with depression show complete remission through optimized treatment, including trials of multiple drugs with and without simultaneous psychotherapy. In the past few decades, most antidepressant discoveries focused on finding faster, safer, and more selective serotonin or norepinephrine receptor targets. In addition, there is an urgent need to develop new approaches to obtain more effective, safer, and faster antidepressants. In 2019, the FDA approved two new antidepressants: Esketamine for refractory depression and Bresanolone for postpartum depression. Esmolamine, a derivative of the anesthetic drug ketamine, was approved by the FDA for the treatment of refractory depression, based on a large number of preliminary clinical studies [ 148 ]. For example, several randomized controlled trials and meta-analysis studies showed the efficacy and safety of Esketamine in depression or treatment-resistant depression [ 26 , 149 , 150 ]. Although both are groundbreaking new interventions for these debilitating diseases and both are approved for use only under medical supervision, there are still concerns about potential misuse and problems in the evaluation of mental disorders [ 151 ].

To date, although several potential drugs have not yet been approved by the FDA, they are key milestones in the development of antidepressants that may be modified and used clinically in the future, such as compounds containing dextromethorphan (a non-selective NMDAR antago–nist), sarcosine (N-methylglycine, a glycine reuptake inhibitor), AMPAR modulators, and mGluR modulators [ 152 ].

Neuromodulation Therapy

Neuromodulation therapy acts through magnetic pulse, micro-current, or neural feedback technology within the treatment dose, acting on the central or peripheral nervous system to regulate the excitatory/inhibitory activity to reduce or attenuate the symptoms of the disease.

ECT is one of most effective treatments for depression, with the implementation of safer equipment and advancement of techniques such as modified ECT [ 153 ]. Mounting evidence from randomized controlled trial (RCT) and meta-analysis studies has shown that rTMS can treat depressive patients with safety [ 154 ]. Other promising treatments for depression have emerged, such as transcranial direct current stimulation (tDCS) [ 155 ], transcranial alternating current stimulation (tACS)[ 156 ], vagal nerve stimulation [ 157 ], deep brain stimulation [ 158 ] , and light therapy [ 159 ], but some of them are still experimental to some extent and have not been widely used. For example, compared to tDCS, tACS displays less sensory experience and adverse reactions with weak electrical current in a sine-wave pattern, but the evidence for the efficacy of tACS in the treatment of depression is still limited [ 160 ]. Alexander et al . recently demonstrated that there was no difference in efficacy among different treatments (sham, 10-Hz and 40-Hz tACS). However, only the 10-Hz tACS group had more responders than the sham and 40-Hz tACS groups at week 2 [ 156 ]. Further RCT studies are needed to verify the efficacy of tACS. In addition, the mechanism of the effect of neuromodulation therapy on depression needs to be further investigated.

Precision Medicine for Depression

Optimizing the treatment strategy is an effective way to improve the therapeutic effect on depression. However, each individual with depression may react very differently to different treatments. Therefore, this raises the question of personalized treatment, that is, which patients are suitable for which treatment. Over the past decade, psychiatrists and psychologists have focused on individual biomarkers and clinical characteristics to predict the efficiency of antidepressants and psychotherapies, including genetics, peripheral protein expression, electrophysiology, neuroimaging, neurocognitive performance, developmental trauma, and personality [ 161 ]. For example, Bradley et al . recently conducted a 12-week RCT, which demonstrated that the response rate and remission rates of the pharmacogenetic guidance group were significantly higher than those of the non-pharmacogenetic guidance group [ 162 ].

Subsequently, Greden et al . conducted an 8-week RCT of Genomics Used to Improve Depression Decisions (GUIDED) on 1,167 MDD patients and demonstrated that although there was no difference in symptom improvement between the pharmacogenomics-guided and non- pharmacogenomics-guided groups, the response rate and remission rate of the pharmacogenomics-guided group increased significantly [ 163 ].

A recent meta-analysis has shown that the baseline default mode network connectivity in patients with depression can predict the clinical responses to treatments including cognitive behavioral therapy, pharmacotherapy, ECT, rTMS, and transcutaneous vagus nerve stimulation [ 164 ]. However, so far, the biomarkers that predict treatment response at the individual level have not been well applied in the clinic, and there is still a lot of work to be conducted in the future.

Future Perspectives

Although considerable progress has been made in the study of depression during a past decade, the heterogeneity of the disease, the effectiveness of treatment, and the gap in translational medicine are critical challenges. The main dilemma is that our understanding of the etiology and pathophysiology of depression is inadequate, so our understanding of depression is not deep enough to develop more effective treatment. Animal models still cannot fully simulate this heterogeneous and complex mental disorder. Therefore, how to effectively match the indicators measured in animals with those measured in genetic research or the development of new antidepressants is another important challenge.

Change history

17 may 2021.

A Correction to this paper has been published: https://doi.org/10.1007/s12264-021-00694-9

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Acknowledgments

This review was supported by the National Basic Research Development Program of China (2016YFC1307100), the National Natural Science Foundation of China (81930033 and 81771465; 81401127), Shanghai Key Project of Science & Technology (2018SHZDZX05), Shanghai Jiao Tong University Medical Engineering Foundation (YG2016MS48), Shanghai Jiao Tong University School of Medicine (19XJ11006), the Sanming Project of Medicine in Shenzhen Municipality (SZSM201612006), the National Key Technologies R&D Program of China (2012BAI01B04), and the Innovative Research Team of High-level Local Universities in Shanghai.

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Zezhi Li, Jun Chen & Yiru Fang

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Meihua Ruan

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Li, Z., Ruan, M., Chen, J. et al. Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications. Neurosci. Bull. 37 , 863–880 (2021). https://doi.org/10.1007/s12264-021-00638-3

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Two Decades of Anxiety Neuroimaging Research: New Insights and a Look to the Future

• Alexander J. Shackman , Ph.D. ,
• Andrew S. Fox , Ph.D.

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Anxiety is widely conceptualized as a state of heightened distress, arousal, and vigilance that can be elicited by potential threat ( 1 , 2 ). When extreme or pervasive, anxiety can be debilitating ( 3 ). Anxiety disorders are among the leading cause of years lived with disability, afflicting ∼300 million individuals annually ( 3 ). In the United States, nearly 1 in 3 individuals will experience an anxiety disorder in their lifetime, diagnoses and service utilization are surging among young people, and direct health care costs exceed $40 billion annually ( 3 – 6 ). Yet existing treatments are inconsistently effective or are associated with significant adverse effects, underscoring the urgency of developing a clearer understanding of the underlying neurobiology ( 7 , 8 ).

Perturbation and recording studies in rodents and monkeys have begun to reveal the specific molecules and microcircuits that control defensive responses to a variety of threats ( 9 ), but the relevance of these discoveries to the complexities of the human brain and human anxiety is unclear. Human neuroimaging research provides an opportunity to address this translational conundrum. Clinical studies of anxiety have leveraged a variety of experimental challenges—from aversive photographs and other symptom provocations to threat conditioning and trauma recall paradigms—to identify aspects of brain function that discriminate individuals with pathological anxiety from control subjects. Preclinical human studies of anxiety have taken a different tack and narrowly focused on tracing the circuits normatively engaged by the anticipation of potential threat in nominally healthy samples. Preclinical studies are essential for understanding how anxiety normally works, free from the confounders, comorbidities, and sequelae of psychiatric disease and treatment. They provide a translational bridge to mechanistic studies in animals, which also tend to focus on adaptive behavioral responses (e.g., freezing) to threat. And because they capture symptoms and intermediate phenotypes—such as subjective feelings of anxiety—that cut across disorders, human preclinical studies provide a unique opportunity to develop transdiagnostic biomarkers ( 10 , 11 ). While clinical and preclinical studies both provide valuable clues about the neural underpinnings of anxiety, as the literature has grown, it has become increasingly difficult to integrate the two veins of research into a unified conceptual framework.

In this issue of the Journal , Chavanne and Robinson ( 12 ) provide the most comprehensive coordinate-based meta-analysis of anxiety-related functional neuroimaging research in over a decade ( 13 ), focusing on studies of emotion perception and provocation (156 studies with 693 preclinical participants, 2,554 case subjects, and 2,348 control subjects). Their clinical meta-analyses included patients with generalized anxiety disorder, social anxiety disorder, specific phobia, panic disorder, posttraumatic stress disorder, and mixed anxiety diagnoses. Preclinical analyses included coordinates culled from a variety of unpredictable or uncertain threat studies (e.g., threat of shock). Notably, the authors have made their raw data ( https://osf.io/9s32h ) and meta-analytic maps ( https://neurovault.org/collections/6012 ) freely available, facilitating a range of applications by other investigators.

The publication of Chavanne and Robinson’s report provides an opportune moment to take stock of what we have learned from 20 years of anxiety-related neuroimaging research and to identify the most fruitful next steps.

Chavanne and Robinson show that clinical anxiety is associated with heightened reactivity in an extended subcortico-cortical circuit. Subcortically, this encompasses several regions implicated in animal models of anxiety, including regions of the amygdala, anterior hippocampus, and periaqueductal gray ( 9 ). The bed nucleus of the stria terminalis (BST)—another key player in animal models of anxiety that has only recently begun to attract the attention of the psychiatric imaging community ( 9 , 14 )—was also evident in secondary analyses that excluded medicated patients. In the cortex, Chavanne and Robinson show that clinical anxiety is associated with elevated reactivity in the dorsolateral prefrontal cortex, pregenual anterior cingulate cortex, midcingulate cortex, and anterior insula. Collectively, these observations replicate and extend Etkin and Wager’s influential 2007 neuroimaging meta-analysis ( 13 ), which identified heightened amygdala and insula reactivity as a potential “final common pathway” for pathological anxiety.

A key feature of Chavanne and Robinson’s report is the systematic analysis of preclinical studies of anxiety. This revealed a circuit encompassing many of the regions identified by their clinical analyses—including the BST, periaqueductal gray, midcingulate cortex, and anterior insula—an observation consistent with models suggesting that pathological anxiety reflects sensitization of the circuitry responsible for orchestrating normative states of anxiety ( 1 , 2 ). Chavanne and Robinson also provide exciting new evidence that uncertain and certain threat recruit an overlapping core network in humans ( Figure 1 ). Since the time of Freud, the heuristic distinction between uncertain (“anxiety”) and certain (“fear”) threat has been a hallmark of neuropsychiatric models of emotion ( 15 ), including the National Institute of Mental Health’s Research Domain Criteria framework, but the underlying neurobiology has remained contentious ( 16 ). Leveraging data from Fullana and colleagues’ recent meta-analysis of preclinical “fear conditioning” studies ( 17 )—the prototypical laboratory assay of “fear”—Chavanne and Robinson show that certain and uncertain threat are processed in co-localized regions of the periaqueductal gray, BST, midcingulate cortex, and anterior insula, a finding that neatly dovetails with other recent work in humans and rodents ( 9 , 16 ). These observations reinforce claims that “anxiety” and “fear” are more biologically alike than different and reflect the operation of a shared set of neural building blocks ( 16 ).

FIGURE 1. Preclinical studies of uncertain threat anticipation and “fear conditioning” recruit a common circuit a

a The figure summarizes the results of two coordinate-based meta-analyses. The inset at bottom right depicts meta-analytic results for the 18 preclinical anxiety studies used in Chavanne and Robinson’s analysis ( 12 ) and highlights regions showing greater activity during uncertain-threat anticipation (threat > safe; https://neurovault.org/collections/6012 ). The inset at top left depicts meta-analytic results for the 27 preclinical “fear conditioning” studies used in Fullana and colleagues’ analysis ( 17 ) and highlights regions showing greater activity during threat anticipation (CS+ > CS−; https://neurovault.org/collections/2472 ). Results (red clusters) suggest that the anticipation of both threats elicit qualitatively similar patterns, including heightened activity in the region of the bed nucleus of the stria terminalis (BST). This impression is reinforced by the substantial correlation between the two whole-brain patterns (r values, 0.66–0.69 across different measures of standardized effect size). For illustrative purposes, every 10th voxel is depicted in the scatterplot.

Remarkably, the amygdala was not evident in either Chavanne and Robinson’s or Fullana and colleagues’ preclinical meta-analytic results ( Figure 1 ). Why? It may reflect the systematic exclusion of studies that relied on popular small-volume significance thresholds and region-of-interest approaches. It may reflect systematic differences in the kinds of tasks used in preclinical and clinical anxiety research (e.g., shock anticipation versus emotional faces). Or it may simply reflect insufficient power to declare modest effects “whole-brain significant” in individual studies (i.e., the median sample size was <30). Consistent with this possibility, preclinical studies using larger samples and improved techniques for data acquisition and processing have shown that the dorsal amygdala (in the region of the central nucleus) is engaged by uncertain and certain threat anticipation, consistent with perturbation studies in animals ( 9 , 16 ).

In sum, two decades of neuroimaging research demonstrate that anxiety disorders are associated with exaggerated reactivity to emotional challenges in regions of the amygdala, BST, periaqueductal gray, midcingulate cortex, and anterior insula. This extended circuit is recruited by uncertain (“anxiety”) and certain (“fear”) threat in nominally healthy individuals, suggesting that clinical and preclinical studies are tapping a common process. The subcortical components of this core anxiety circuit show an encouraging degree of convergence with those implicated by mechanistic work in rodents, monkeys, and humans ( 1 , 9 ). Furthermore, Chavanne and Robinson’s careful follow-up analyses make it unlikely that these results are an artifact of publication biases.

Nevertheless, Chavanne and Robinson’s report serves as a sober reminder that most of the work necessary to understand the brain bases of human anxiety remains undone. Anxiety is a multifaceted construct that includes alterations in subjective distress, cognition, arousal, and behavior that cut across multiple timescales and disorders ( 1 , 2 , 18 ). It is unclear how the extended anxiety circuit relates to these narrower facets and whether particular circuit components or their functional interactions causally contribute to the development and maintenance of psychopathology. It is also unclear whether hyperreactivity in this circuitry is specific to anxiety disorders or extends more broadly to encompass the internalizing spectrum. In the specific case of the amygdala, the latter appears to be true ( 19 , 20 ), an observation consistent with the efficacy of antidepressants for both depression and most anxiety disorders ( 7 , 8 ).

Although diagnostic differences are possible, Chavanne and Robinson acknowledge that more data are needed. At present, valid inferences are thwarted by the limited number of studies available for many diagnoses and by differences in both power and paradigm across diagnoses. Indeed, their meta-analyses included ∼3 times more studies of social anxiety disorder (k=41) than panic disorder (k=14), with systematic differences in the tasks used to probe particular diagnoses (e.g., emotional faces versus symptom provocation). The hazard of glossing over diagnosis-task confounders is underscored by Chavanne and Robinson’s supplementary meta-analyses of cognitive tasks, which revealed radically different correlates of pathological anxiety compared with those evident for emotion tasks (e.g., midcingulate cortex hyporeactivity in patients). Widespread comorbidity and inadequate diagnostic reliability further muddle matters ( 21 , 22 ). Along these lines, it is also unclear whether observed differences in BST reactivity across Chavanne and Robinson’s meta-analyses reflect differences in population, power, or paradigm. These limitations are not specific to Chavanne and Robinson’s study; they cut across much of the literature and afflict other recent meta-analyses ( 19 , 20 ).

Overcoming these challenges will require larger and more diagnostically diverse samples and an emphasis on more reliable dimensional approaches ( 21 , 22 ). The development and application of tasks optimized for theory-driven computational modeling would provide important opportunities for understanding the mechanisms that promote extreme anxiety in humans (e.g., aberrant processing of risk or threat ambiguity), clarifying the functional contribution of specific components of the extended anxiety circuit (e.g., BST versus midcingulate cortex), and facilitating translation between human and animal research ( 23 ).

Chavanne and Robinson’s observations raise the possibility that hyperreactivity of the extended anxiety circuit could be used as an objective transdiagnostic biomarker. Determining whether this neural “signature” possesses the requisite reliability, sensitivity, and specificity will require more sophisticated machine learning approaches and larger, more diverse samples ( 10 , 11 ). Development of anxiety-related biomarkers has the potential to enable preclinical tests of target engagement and to expedite the development of new treatments. To the extent that biomarker development is centered on a dimensional outcome that cuts across disorders, like anxious distress, it will be important to demonstrate generalizability across elicitors and tasks.

Two decades of human neuroimaging research have yielded steady advances in our understanding of the neural systems underlying adaptive and maladaptive anxiety. Chavanne and Robinson’s observations highlight the relevance of a core circuit encompassing a mixture of the “usual suspects” (amygdala and anterior insula) and some less familiar actors (BST, periaqueductal gray, and midcingulate cortex). Despite this progress, the mechanisms that cause pathological anxiety remain uncertain, and existing treatments remain far from curative for many. Addressing these challenges will require an increased investment in anxiety research, one commensurate with the staggering burden that anxiety disorders impose on global public health, and an enhancement of coordination of human and animal research. The latter could be achieved by combining perturbation techniques in animals with the same neuroimaging strategies routinely used in humans, enabling the development of bidirectional translational models ( 9 ). Nonhuman primate models are likely to be especially informative for understanding cortical components of the extended anxiety network, given uncertain or absent anatomical homologies in rodents ( 24 ). Finally, a greater emphasis on dimensional phenotypes and computational approaches promises to further accelerate efforts to alleviate the suffering caused by pathological anxiety.

Supported in part by the California National Primate Center; NIH grants DA040717, MH107444, MH121409, MH121735; University of California, Davis; and University of Maryland, College Park.

The authors report no financial relationships with commercial interests.

The authors acknowledge assistance from K. DeYoung, L. Friedman, and J. Smith.

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• Ned H. Kalin , M.D.

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Neuroscience-based psychotherapy: A position paper

Davide maria cammisuli.

1 Department of Psychology, Catholic University, Milan, Italy

Gianluca Castelnuovo

2 Psychology Research Laboratory, Istituto Auxologico Italiano IRCCS, Milan, Italy

In the recent years, discoveries in neuroscience have greatly impacted upon the need to modify therapeutic practice starting from the evidence showing some cerebral mechanisms capable of coping with mental health crisis and traumatic events of the individual's life history by redesigning the narrative plot and the person's sense of the Self. The emerging dialogue between neuroscience and psychotherapy is increasingly intense and modern psychotherapy cannot ignore the heritage deriving from studies about neuropsychological modification of memory traces, neurobiology of attachment theory, cognitive mechanisms involved in psychopathology, neurophysiology of human empathy, neuroimaging evidence about psychotherapeutic treatment, and somatoform disorders connecting the brain and the body. In the present article, we critically examined sectorial literature and claimed that psychotherapy has to referred to a neuroscience-based approach in order to adopt the most tailored interventions for specific groups of patients or therapy settings. We also provided recommendations for care implementation in clinical practice and illustrated challenges of future research.

1. Introduction

In the second half of the 19th century, schools in psychotherapy were born according to different epistemological constructs and methods, with the aim of removing trauma, modifying symptoms of affective nature, and promoting the development of a healthy personality (Janiri et al., 2009 ). Psychotherapy can be defined in relation to three main elements, that is a helping relationship established after the parent–child one, the creation of a secure base from which the therapist influences the patient through psychological techniques, and a patient who has the capacity to benefit from such an experience (Strupp, 1978 ). However, Freud himself first recognized the limit of the only adoption of a pure introspective approach, stating that the deficiency in [our] description would probably vanish if we were already in a position to replace the psychological terms by physiological or chemical ones (Freud, 1920 , p. 60). He first endeavored to establish the restraint of the “ talking cure ” and to clarify that the progress of what we currently name as “neuroscience” would have achieved the result to bridge this gap (Solms and Turnbull, 2018 ).

With the advent of neuroscience, a highly integrated discipline, as well as astrophysics, knowledge in the fields of molecular and cellular biology, biochemistry, neurophysiology, neuroradiology, and general and experimental psychology, has harmoniously merged, creating a body of evidence of which psychotherapy has to benefit. One of the most fruitful experiences that determined a new approach to scientific research in brain science was that of Francis O. Schmitt, who set up the Neuroscience Research Program (NRP) at the Massachusetts Institute of Technology (MIT) in 1962. He intended the NRP as a research field connecting physical, biological, and neural science for a better understanding of the liaison between mind, brain, and behavior (Adelman, 2010 ). Neuroscience grew rapidly from this time point on as scientists from all areas of the life sciences rapidly moved into the field. This process culminated with the foundation of the Society for Neuroscience (SfN) in 1969 (Adelman, 2010 ).

An important turnover in the process of the emerging dialogue between psychotherapy and neuroscience was undoubtedly the scientific contribution of Kandel ( 1998 , 2012 ), who went on to the Nobel Prize for medicine/physiology in 2000 by providing a breakthrough perspective on how biology has influenced modern psychiatry, especially on how memory and learning processes can explain behavior and its disorder and implications of the neurobiological research in psychotherapy. Kandel's description of the influence of culture on genetics and of the mechanism of “reconsolidation” of memory emphasizes the importance of psychotherapy for mental disorders. Particularly, practicing psychotherapy as a strategic and significant influence on the patient's living environment can be particularly effective in modeling gene expression and promoting behavioral modifications (Etkin et al., 2005 ).

Beyond different treatment approaches (i.e., psychoanalysis and psychodynamic therapies, cognitive–behavioral therapy, humanistic therapy, family and system psychotherapy, interpersonal psychotherapy, and integrative or holistic therapies) (Roth and Fonagy, 2005 ), psychotherapy involves common elements, such as verbal and non-verbal exchanges as interactions between therapist and patient, therapeutic alliance, empathy, resilience to trauma, cognitive restructuring, and new learning (Gabbard, 2009 ) that we currently believe psychotherapists have to read under the magnifying glass of neuroscience. Currently, on at least six major study areas, some of which already pointed out in Janiri et al. ( 2009 ), neurosciences have provided valuable contributions to the understanding of the neurobiological substrate of brain changes useful for psychotherapy practice: memory of trauma, neurobiological correlates of human attachment, mirror neurons system and theory of mind (ToM), brain modifications after psychotherapeutic treatment, and somatic symptoms and disorders. To let the scientific audience better focus on these areas, we provided a summary table for each section of the manuscript reporting major recommendations for mental health practitioners. We firmly affirm that psychotherapists in the modern era can no longer ignore discoveries in the field of neuroscience and have to learn from them in order to implement their clinical practice.

2. Psychotherapy of traumatic memories

There are organic molecular mechanisms that are fundamental for the establishment of long-term memories. For instance, the corticosterone hormone, which corresponds to the cortisol in humans, released after a stressor input in animals, rapidly interacts with growth factors produced in the brain, in particular with the brain-derived neurotrophic factor (BDNF), a neurotrophin essential for long-term synaptic plasticity (Alberini, 2009 ). These mechanisms occur in the medial temporal lobe, specifically in the hippocampus, which plays a central part in long-term memory formation (Johnston and Amaral, 2004 ). Peripheral BDFN levels are lower in psychiatric disorders (Boulle et al., 2012 ), and a recent systematic review has shown that BDNF seems to present variations after psychotherapy, especially in patients with bulimia, post-traumatic stress disorder (PTSD), insomnia, and borderline personality disorder, with a reduction in symptomatology (Claudino et al., 2020 ).

Memory represents a system of brain networks that presides over different functionally coordinated and anatomically independent cognitive mechanisms sharing the ability to store information (Squire, 2004 ). Particularly, explicit (or declarative) memory is involved in the psychotherapeutic process. As reported in Freud-Fliess Letters (1887–1904), Our psychic mechanism is formed, is created through a process of stratifications. The material that is present as memory or trace of memory undergoing continuous reconstruction, a renewal with respect to the present, to new circumstances. Memory is not present once, it does not remain as a single trace but continues to renew itself (Albertini, 2014 ). Research in neuroscience has documented that the storage of memories is allowed in relation to a certain level of stress (Schwabe et al., 2012 ). When the stress level is relatively moderate, memories are formed and retained, and when the stress becomes too prolonged or intense, it generates a negative effect on memories that can even be lost, like in the case of trauma (Alberini, 2011 ). Moreover, regardless of its valence (i.e., positive vs . negative), the intensity of an emotion experienced during an original event increases the likelihood that the memory will be recalled later. Scientific evidence has shown that an increased arousal results in a more augmented physiological interaction between the amygdala and the hippocampus, leading to an enhanced encoding and long-term consolidation of information (Lane et al., 2015 ).

Starting from these findings, it is possible to advance hypotheses on the mechanisms that take place in the room of the psychotherapist when memories are remembered by the patient, precisely traumatic ones. Reconsolidation mechanisms would offer the opportunity to restore memories with a different emotional level, that is, lower stress intensity and greater control. At a molecular level, memory consolidation of an experienced event (i.e., long-term memory) is formed as synaptic connections within a set of neurons (Gallistel and Matzel, 2013 ). To this end, an experienced event induces a neuronal depolarization and an influx of intracellular Ca 2+ , which initiates a downstream molecular cascade that results in the transcription and translation of plasticity-related proteins (PRPs) inducing changes in neuronal networks as remodeled synaptic connections (Sekeres et al., 2017 ). The activity among synaptic connections leads to the development of “memory engram” requiring a period of quiescence to be stabilized that can be potentially interrupted by protein-synthesis inhibition or interference from new learning (Sekeres et al., 2017 ). The multiple trace theory (MTT) (Nadel and Moscovitch, 1997 ; Moscovitch and Nadel, 1999 ) offers insight into how the repeated recollection of prior events can transform memory representations. Accordingly, the establishment of long-term memory involves a long interaction between hippocampal regions of the medial temporal lobes and medial prefrontal cortex. MTT proposes that each time an episodic memory is elicited by active retrieval or recollection, an update trace is created, incorporating information from the old trace and new recall. According to Albertini ( 2014 ), remembering with the psychotherapist creates the possibility of associating old reactivated memories with new ones moving from painful experiences faced during treatment. In the presence of new elements and of the support given by the therapist, restored memory has different qualities (i.e., less traumatic and emotionally intense). MTT supports that memories are not the same record of the original event but undergo updating and reshaping as they age and when they are altered by recollection during psychotherapy (Lane et al., 2015 ). The psychotherapeutic process promotes the possibility of associating old memories reactivated with new experiences of the present, thus soliciting a real behavioral change (Lane, 2020 ).

A number of psychotherapeutic techniques are considered in the emerging field of “memory therapeutics” including accelerated resolution therapy, rewind techniques, cognitive restructuring, and imagery modification. They aim to help the patient to feel less distressing sensations during memory reactivation, achieve a novel perspective about past negative events, rescript a different ending, and transform trauma using metaphors (Waits and Hoge, 2018 ). Since memory traces of traumatic events can be weakened, it is helpful to underline the influence of experiences made during psychotherapeutic treatment. Specifically, a distinct type of successful traumatic memory processing in PTSD psychotherapy includes threat processing by intensive imaginal memory retrieval through the support of the therapist for the reappraisal of the event, self-referential reflection on associated beliefs and emotions, and memories retelling (Ford, 2018 ).

• The BDNF—which is related to synaptic plasticity—seems to be low in psychiatric disorders;
• A moderate level of stress is necessary for memory storage;
• Memory reconsolidation supports the psychotherapeutic process for the creation of alternative ways of behaving; and
• Psychotherapy of traumatic memories consists of specific techniques in the case of PTSD.

3. Neurobiology of attachment therapy

According to Holmes ( 1993 ), attachment theory provides a psychological grounding that is applicable to all forms of psychotherapy in terms of a secure base (i.e., consistency, regularity, and reliability, a combination of warmth and firm boundaries), emersion of autobiographical competence (i.e., a secure attachment in therapy enables the patient to tell a different story about himself/herself), ability in processing affect (i.e., primitive emotions aroused in therapy are modulated by the attunement of the therapist and become manageable for the patient), and coping with loss (i.e., the expression of repressed pain or the modulation of unprocessed angry is an important part of each psychotherapeutic treatment). Attitudes and behavioral modifications of parents during the maternal gestational period, childbirth, breastfeeding, and in the first 3 years of the child's life imply a synergy between hormonal and neurochemical systems and lead to changes in brain structure and functionality, stimulating or inhibiting certain brain areas (Kim, 2016 ; Grumi et al., 2021 ). Early life experiences with the own caretakers have a huge impact on the child's brain development because repeated relationship patterns shape undifferentiated neurons into coherent firing networks supporting specific cognitive-affective brain structures (Schore, 2003 ; Kandel et al., 2013 ; Grawe, 2017 ; Siegel, 2020 ). The attachment relationship between the baby and the primary caretakers represents the link between the neurobiological programming of brain development and early care experiences. The child's bond to caregivers is implicated in the development of the right hemisphere and of specific brain areas (i.e., prefrontal cortex, orbitofrontal cortex, and limbic system) conditioning interpersonal relationships. In fact, such brain areas are involved in the processing and expression of emotional information and influence affective states' modulation and decoding of facial expressions, gestures, and prosody (Etkin et al., 2015 ). Remarkably, starting from a neuropsychoanalysis perspective, Schore ( 2022 ) contended that the right brain represents the psychobiological substrate of the unconscious human mind, as first described by Sigmund Freud, able to process emotional stimuli with implicit attention outside the role of awareness. Early relational experiences with caretakers are transferred into the psychotherapeutic process. Maternal and paternal mental illnesses in the perinatal period negatively impacting the interaction with the baby represent risk factors for the development of the parenting style because they may inhibit the abovementioned child's brain areas (Stein et al., 2014 ; Lautarescu et al., 2020 ). Conversely, when parental care contemplates the growth needs of the child, and neuronal networks conform to ensure positive responses to the environment, adults presenting with secure attachment show higher levels of reflective functioning and mature defenses that serve in better regulating affective states than those with insecure attachment (Tanzilli et al., 2021 ).

3.1. Perinatal psychotherapy

With the acronym Perinatal Mood and Anxiety Disorder (PMAD), a consensus in the scientific community has been obtained about the need to go beyond a focus on postpartum depression in the perinatal period toward a more comprehensive mother' symptomatology, including the spectrum of depressive and anxiety disorders, the obsessive–compulsive disorder, the PTSD and the puerperal psychosis (Byrnes, 2018 ). Furthermore, fathers may display anxiety disorders, somatic symptoms, hypochondria, substance abuse, and behavioral reactivity as maladaptive responses to paternity (Baldoni and Giannotti, 2020 ). To address these issues, perinatal psychotherapy assumes a fundamental part in caretakers' health regarding manifestations of mental suffering, starting from the multifactorial etiopathogenetic origin of maternal and parental mental illnesses, including neurobiological and hormonal modifications due to childbirth. The activation of the superior temporal sulcus, the amygdala, the right inferior frontal gyrus, and the insula is particularly sensitive to changes in hormonal levels involved in parental care, including augmentation in oxytocin and vasopressin levels in both parents and decrement in testosterone and estradiol for men (Abraham et al., 2014 ; Witteman et al., 2019 ). Interesting advances in psychotherapy research have recently highlighted the role of some hormones, such as cortisol and oxytocin, in mediating the relationship between the therapist and the patient, too. The cortisol, or the stress hormone representing the final product of the hypothalamic–pituitary–adrenal axis, is secreted in psychosocial stress contexts (Dickerson and Kemeny, 2004 ) and is capable of modulating the emotional experience influencing the affect. For instance, higher cortisol levels are associated with significant increases in negative affect in patients with major depressive disorder (MDD) (Booij et al., 2016 ). Levi et al. ( 2021 ) have studied the extent to which therapist's cortisol modulates patient's affect during psychodynamic psychotherapy of MDD by collecting salivary samples before and after specified sessions and data from patient's retrospective reports of in-session affect. The study provided initial evidence that the positive or negative affect of the patient is mediated by the therapist's changes in cortisol levels, supporting the importance of a special social support context built by the interpersonal relationship as an empathic response to the stress manifested by depressed patients. When in a safe situation, a person profoundly perceives his/her engagement, the oxytocin may also be released, supporting reciprocity, empathy, compassion, and synchronized behavior and characterizing parent–infant relationship (Schneiderman et al., 2012 ; Feldman, 2017 ). Oxytocin, as the neurohormone associated with care behavior, is implicated in the pathophysiology of MDD in humans (Engel et al., 2019 ), too, and it is a potential candidate for explaining treatment outcomes in relation to patient–therapist synchrony. Zilcha-Mano et al. ( 2020 ) have demonstrated that psychotherapeutic treatment is effective when patients suffering from MDD and therapists are biologically synchronized in oxytocin levels change, giving cutting-edge directions for future research. Starting from these preliminary findings, we think that psychotherapists working on perinatal mental health should reflect on how they build a supportive context and place themselves in sync with the patient since this can actually affect his/her affective state with significant implications for the child's care.

3.2. Couple psychotherapy

The integration of the attachment theory with neuroscience also poses a relevant application in the psychotherapy of couples about the dyadic affect regulation during treatment. The goal of neuroscience-based psychotherapy in this specific setting is to help each partner understand his/her part in altering the relationship, starting from personal attachment needs and psychophysiological reactions elicited in the communication with the significant other. By understanding how each partner's nervous reaction is affected by emotional reverberation triggered in the couple's interaction, partners can be treated in psychotherapy to recreate greater emotional control and a secure relationship base (Goldstein and Thau, 2004 ). When a couple's attachment schema is breached, partners may seek treatment, and psychotherapy plays a pivotal role in restoring a balance between them. Particularly, they should be encouraged to become progressively aware of their unconscious, implicit memories driving personal communication patterns (Schore, 2003 ). In this way, when partners get into a crisis and start psychotherapy, they are stimulated to progressively recognize the subcortical emotional system they have constructed during the love affair in order to rebuild it in a creative and positive manner. The therapist has to be able to normalize conflictual states by soliciting the couple to pay attention to autonomic responses to dangerous, frightening, and disruptive stimuli, which may be conveyed in the communication between partners, in order to control them and promote assertiveness.

• An attachment-based approach in psychotherapy looks at the connection between the infant's primary experiences and caregivers' responses;
• The development of the right hemisphere and of the prefrontal cortex, orbitofrontal cortex, and limbic system is influenced by such a relationship in childhood;
• Perinatal psychotherapists should pay attention to neurochemical and hormonal modifications in new parents;
• The awareness of the subcortical emotional system driving interpersonal communication between partners is a goal of neuroscience-based couple psychotherapy.

4. Cognitive psychopathology and psychotherapy

Cognitive defect varies to some extent in psychiatric disorders (Millan et al., 2012 ). However, it is still unclear how cognitive deficits may limit the ability of patients to actually attend psychotherapy or how cognitive problems may preclude a positive response to treatment. Cognitive symptoms such as those related to frontal lobe damage provoke a series of cognitive (e.g., disturbances in attention, planning, rigidity, inertia, criticism, control, inhibition, and decision-making) and emotional deficits (e.g., apathy, abulia, anhedonia, impulsiveness, behavioral inadequacy, aggression, and sociopathy) can greatly impact psychological interventions in patients with neurological disorders (Robinson et al., 2019 ) or acquired brain injury (Thøgersen et al., 2022 ). Psychotherapists have to be aware of executive dysfunction hindering the therapeutic process as an impairment that can strongly restrain its effect (Diamond, 2013 ; Cozolino, 2017 ), specifically in the case of particular approaches designed for older adults because of diminished specific frontal skills reported in elderly (Goodkind et al., 2016 ).

In this context, cognitive psychopathology offers an original contribution to psychotherapy for an in-depth understanding of psychiatric disturbances by making available the broad patrimony inherited from modern clinical neuropsychology (Timpano Sportiello, 2008 ). In particular, it can contribute to improving psychotherapeutic practice by refining the diagnosis and the differential diagnosis, offering relevant information to be provided to psychiatrists in the case of patients following combined treatments (i.e., neuropsychopharmacology), and enhancing the reliability of the prognostic judgment, also in relation to psychosocial rehabilitation interventions (e.g., behavioral skills training in psychiatric disorders). Cognitive dysfunction predicts psychosocial impairment; thus, its assessment is fundamental for rehabilitation purposes, especially in the case of severe psychiatric diseases (Etkin et al., 2022 ).

Disturbances in autobiographical memory, reality testing, interpretation of others, and fragmentation of a person's thought as an individual apart from everyone else are the consequences of the disruption of the “Default Mode Network” (DMN) (Raichle and Snyder, 2007 ; Andrews-Hanna et al., 2014 ; Mak et al., 2017 ) and are present in anxiety, depression, PSTD, and schizophrenia (Broyd et al., 2009 ; Cozolino, 2017 ). Neural areas, including the medial prefrontal cortex, the midline regions of the posterior cingulate cortex, and the precuneus region of the parietal cortex that turned on/off only to self-related task engaging of an individual, have been recently shown to support the DMN (Raichle and Snyder, 2007 ; Mak et al., 2017 ; Buckner and DiNicola, 2019 ). These findings have sustained the hypothesis that it may be the neuronal basis of the Self (i.e., personal and social awareness and ability in differentiated cognition and perception) (Faustino, 2022 ). Moreover, the dorsolateral prefrontal cortex, which is considered the neural circuit of working memory, also enables us to pay attention to something in the here-and-now (Siegel, 2006 ). Results are fundamental in psychotherapy—especially in Gestalt therapy—because its normal functioning permits to place the basis for the correct understanding of present feelings, emotions, and interpersonal reactions as they occur in the ongoing treatment sessions with no or little emphasis on past experiences. In a few words, it allows patients to concentrate on a new way of behaving built together with the psychotherapist.

The cognitive psychopathology perspective proposes that cognitive dysfunctions, which are closely related to emotional and relational processes, may contribute to the development, maintenance, and recurrence of psychiatric symptoms (Seron and Van der Linden, 2000 ). Psychotherapists must be exercised in drawing specific conclusions from a deep investigation of patients, including their cognitive evaluation, with the aim of taking into account particular mechanisms associated with mental pathology during the treatment course. Cognitive impairment consisting of dysfunction in working memory, attention/executive functions, processing speed, and visual and verbal learning represents a core feature of schizophrenia that is present in 62%−98% of patients and has been described in the first psychiatric episode, in healthy close relatives and in persons at high risk of developing the disease, and both in ongoing and remission phases (Morozova et al., 2022 ). Anxious symptoms produce significant deficits in attention control efficiency, especially in inhibition and switching (Shi et al., 2019 ). Symptoms frequently complained by depressed patients include attentional lability, concentration difficulties, dysmnesia (e.g., forgetfulness and word-finding difficulty), problem-solving, decision-making, judgment, and mental slowness (Richardson and Adams, 2018 ), whereas cognitive impairment in bipolar disorder is not limited to the affective episodes but persist in euthymic phases and mainly pertain attention, executive functions, learning, memory, and psychomotor speed (Cipriani et al., 2017 ). Patients with obsessive–compulsive disorder are significantly impaired in visuospatial memory, executive functions, verbal memory, and verbal fluency (Shin et al., 2014 ). Poor executive or “top-down regulation” of appetitive (i.e., reward, incentive salience) or aversive (i.e., stress, negative affect) processes is recognized as a basic impairment in behavioral addiction and a potentially relevant target for intervention, too (Ramey and Regier, 2019 ).

Cognitive remediation (CR)—sometimes referred to as cognitive enhancement therapy—is an intervention targeting cognitive deficits using scientific principles of learning in order to improve functional outcomes and rehabilitation of life skills (Wykes, 2018 ). CR has been conducted in various psychiatric disorders. Empirical evidence supports its efficacy in schizophrenia (Vita et al., 2021 ). CR techniques have also been applied to eating and weight disorders, attention-deficit hyperactivity disorders, mood disorders, anxiety disorders, substance use disorders, and autism spectrum disorders (Kim et al., 2018 ). We encourage psychotherapists to practice cognitive remediation techniques before treatment, especially when patients are so ill, in order to train them in promoting reflection on their thinking styles and exploring new strategies for everyday life. Such an approach may decrement the high dropouts rate from treatment, increase engagement in the therapeutic alliance (Tchanturia and Hambrook, 2010 ), and provide an opportunity for extending cognitive improvements to everyday functioning (Wykes, 2018 ) before discussing about feelings and emotions representing the core elements of the psychotherapeutic process.

We also affirm that the relationship with the psychotherapist does not only work because of the emotional bond with the patient but also when the practitioner is able to assign him/her adequate cognitive tasks in real life by taking into account the cognitive biases specifically characterizing personal cognitive profile. Only a correct weighting of what the patient is able to transfer from the therapeutic session to practical life experiences provides a concrete possibility of change. This becomes particularly true for cognitive–behavior psychotherapy (CBT) using homework assignments in order to maximize its effect (Kazantzis et al., 2005 ). Quite recently, a neuroscience-informed cognitive–behavioral approach (i.e., “The Waves of the New ABCs”) was developed to describe a continuous processing of internal and external stimuli that results in emotions, behaviors, and thoughts using the ABCDE model (Field et al., 2015 ), too.

Finally, with specific regard to depression, cognitive psychopathology can offer useful indications for psychotherapeutic treatment. We stress that the medial and orbital prefrontal regions play a key role in mediating the interaction between affective states and cognition: Depressed patients show facilitation of performance when responding to stimuli with a negative emotional tone (Elliott et al., 2002 ). Remarkably, mood-congruent memory (MCM) represents a psychological phenomenon where emotional memory is biased toward contents affectively congruent with a past or current mood (Faul and LaBar, 2022 ). Especially in the case of the MCM phenomenon, we recommend psychotherapists to operate through normalizing a deranged cognitive control process, which determines that information with an adverse emotional tone is recorded and recalled more successfully, contributing, in turn, to mood deflection. In the opinion of the authors, since psychophysiology consists a part of clinical neuroscience (Rabavilas and Papageorgiou, 2003 ), it appears advantageous to monitor psychophysiological variations associated with the MCM phenomenon through the ambulatory technological system (Loeffler et al., 2013 ), in order to allow the patient a more comprehensive appraisal of his/her emotional involvement in remembering evocative stimuli. Biofeedback instrumentation is able to identify maladaptive physiological responding and recognizing of mind-body connections can further facilitate psychotherapeutic progress.

• Cognitive deficits—especially executive ones—may preclude a successful psychotherapeutic treatment;
• The DMN may be recognized as the neuronal basis of the Self and its disruption is present in anxiety, depression, PSTD, and schizophrenia;
• Psychotherapists should assess their patients in terms of cognitive functioning according to the neuropsychological impaired profile typically reported in a specific psychiatric disease;
• CR therapy should be practiced by psychotherapists in the case of patients with serious illnesses prior to the treatment, with the final aim of a better therapy start;
• Homework assignments used in CBT should be formulated according to the potential cognitive deficits reported by patients in treatment; and
• Psychotherapists performing retrieval of memories during treatment should pay attention to the MCM phenomenon in the case of patients suffering from MDD.

5. The therapeutic process of human empathy

The mirror neuron system (MNS) represents a distributed network of brain cells that discharges when a primate performs an action or observes an action performed by a similar one (Jeon and Lee, 2018 ). The MSN plays an important role in imitative behavior, especially in deciphering others' actions. They were originally found in the macaque's brain on the ventral premotor cortex and inferior parietal lobule (IPL) (di Pellegrino et al., 1992 ; Gallese et al., 1996 ; Rizzolatti et al., 1996 ). Later neuroimaging studies revealed corresponding activations in some human brain districts, that is, the prefrontal motor cortex, the areas around the intraparietal sulcus, and the supratemporal sulcus (Jellema and Perrett, 2003 ; Puce and Perrett, 2003 ; Rizzolatti and Craighero, 2004 ; Fogassi et al., 2005 ). Remarkably, the IPL visuo-motor organization receiving visual information from the eyes and somatosensory information from the mouth, the hands, and the arms calls into question the evidence that it may represent the neural basis of the ability to understand the intentions of the actions performed by others (Fogassi et al., 2005 ).

Mirror neurons are not only involved in motor perception but also in interpersonal cognition (Baird et al., 2011 ), suggesting that people perceive emotions in others by activating the same emotional response in themselves (Gallese, 2003 ). Although no conclusive evidence for a “broken mirror theory” has been provided, it has been hypothesized that a neuropathological functioning of the brain structures associated with mentalization deficits may exist in some psychiatric disorders characterized by social-cognitive deficits such as schizophrenia (van der Weiden et al., 2015 ) and autism spectrum disorders (Cattaneo et al., 2007 ; Gallese et al., 2013 ). Deficits in social cognition would depend on the particular function investigated (e.g., social threat and facial recognition) and are associated with characteristic symptoms of specific personality disorders (Herpertz and Bertsch, 2014 ).

Beyond the MSN, the empathy-related processing largely used in the therapeutic relationship also involves the temporo-parietal areas, the prefrontal cortex, and the temporal poles as a neurobiological substrate of the ToM, referring to the metacognitive ability to infer another person's mental state from his/her experiences and behavior (Vogeley et al., 2001 ; Vogeley and Fink, 2003 ; Frith and Frith, 2007 ; Schulte-Rüther et al., 2007 ). Remarkably, the dorsolateral prefrontal cortex strongly participates in the empathic response through emotion regulation and perspective-taking, and such capacities are reflected by brain structural variations in psychotherapists. Domínguez-Arriola et al. ( 2022 ) have demonstrated that psychotherapists display a significantly thicker left dorsolateral prefrontal cortex on the A9/46d region than non-therapists and that it correlates with the Empathic Concern (EC) scale score but not with any of the other psychometric measures adopted in the study. The authors concluded that the greater thickness of this region could reflect a superior tendency to regulate one's affective state in a professional context that demands augmented empathic skills than other jobs.

Scientific evidence on human empathy research is consistent with Kohut's emphasis on the therapeutic understanding of the patient prior to the interpretation of his/her dynamics (Stone, 2005 ). The discovery of mirroring mechanisms generates interesting implications for psychotherapeutic practice. The patient has an innate and programmed capacity to internalize, embody, and imitate the state of another person, and through psychotherapy, he/she can discover himself/herself in the other's mind (Janiri et al., 2009 ). Accordingly, proximity to the patient (i.e., proxemics), bodily movements (i.e., kinesics), and paralanguage (i.e., a no-lexical component of speech) are fundamental dimensions in the therapeutic setting (Cappas et al., 2005 ) that have to be correctly managed by psychotherapists prior to discuss about feelings and emotions (Faustino, 2021 ).

The knowledge of the neurophysiology of human empathy is also fundamental in social behavior, and group psychotherapy can take advantage of it. Psychotherapy can use the power of relationships to help patients increase wellbeing and enhance interactive capacity in familiar and social environments, and group therapy offers a unique setting to this end. According to Badenoch and Cox ( 2010 ), the brain's capacity to change is sensitive to environments providing moderate emotional arousal, attuned interpersonal relationships, and experiences that disconfirm earlier implicit learnings. Furthermore, the practice carried out by a patient in a group setting allows them to observe from their own mind the minds of others and concurs in the ability to elaborate emotional states associated with past memories through increased integration between the middle prefrontal cortex and limbic regions, creating a broader sense of confidence and stability (Siegel, 2007 ) through discussion with the group. As the limbic region becomes more dominated by emotional resonance circuits than in the past, internal and behavioral reactivity to activating stimuli decreases, providing the possibility to experiment with control thanks to the group as a source of response regulation (Badenoch, 2008 ). According to Schermer ( 2010 ), beyond mirroring and identification among group members, therapist attunement and interpretation represent two relevant features of group psychotherapy. The therapist attends the non-verbal and paraverbal communication as an expression of bonding and mutuality that emerge in the group. Since mirror neurons can register shared intentions, goals, and emotions, they impact the ongoing cohesion, norms, affective tone, and objectives of each session. Moreover, when the group is a close-knit one, and the psychotherapist has been able to nourish it, members often feel as if they can anticipate what someone is going to say next in the session, and such an impression is therapeutic because it helps members to feel less alone with their troubles and tuned with each other.

Finally, we also stress that psychotherapy practice based on empathic resonance is highly relevant in re-experiencing distressing life episodes to significantly impact response prevention by restraining patients from the use of unhelpful coping mechanisms and by improving behavioral control. Furthermore, it can exert an emotional regulation upon anger, guilt, and anxiety intensity and provides reassuring experiences that can permanently modify the implicit coding of stressful events. This is particularly true in PTSD, which is characterized by trauma re-experience, emotional numbing, avoidance, and exaggerated arousal (Frans et al., 2005 ). According to Peri et al. ( 2015 ), face-to-face exposure to traumatic memories in a safe environment with the psychotherapist may improve the acquisition of emotion regulation leading the patient to create new associative brain networks. Through the use of such a technique, modulated emotional responses are mirrored back to the patient by the psychotherapist allowing him/her to re-experience painful emotions in a controlled manner.

• The MNS and the ability of the ToM support therapeutic relationship, and psychotherapists should be aware of this;
• The patient can discover himself/herself in the psychotherapist's mind during treatment and better hold his/her negative emotions;
• Group psychotherapy supports empathic resonance among members able to strength attentional control over the limbic system reactivity; and
• The exposure technique to traumatic memories in PTSD should be done in a face-to-face manner between the patient and the psychotherapist in order to improve emotional regulation.

6. Neuroimaging and psychotherapy

Psychotherapy represents a well-established strategy for a large part of psychiatric disorders. Despite this, psychotherapeutic interventions do not equally work for all patients because mechanisms through which they may reduce symptomatology remain difficult to fully understand. However, with the advent of neuroimaging techniques, researchers have new tools to find biomarkers of brain functioning associated with psychotherapeutic treatment or recognized as outcome predictors. Neuroimaging of patients with psychiatric disorders has revealed variances from healthy individuals, such as differences in measures of regional cerebral blood flow (rCBF), changes in local blood oxygenation level dependent (BOLD), brain metabolites levels, and functional connectivity (Weingarten and Strauman, 2015 ). Functional imaging methods comprise several types of modalities, such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). With different advantages and limitations (Peres and Nasello, 2008 ), such techniques share two general approaches to the study of psychotherapy effectiveness, that is, the usage of neuroimaging in the pre/post-treatment and the identification at baseline of brain-based predictors of response to treatment (Weingarten and Strauman, 2015 ).

With regard to the first approach, neurobiological research has shown a shared neural circuitry of emotion dysregulation associated with anxiety and depression. Prefrontal cortical regions, including the anterior cingulate cortex, the dorsomedial and ventromedial prefrontal cortices, as well as dorsolateral and ventrolateral prefrontal cortices, provide a “top-down regulation” over limbic regions (i.e., the amygdala, the hippocampus, and the insula) reacting to emotional information (Fournier and Price, 2014 ). Psychotherapeutic techniques relying on cognitive mechanisms associated with frontal domains, such as logical reasoning (e.g., emotions labeling), problem-solving, cognitive reappraisal, cognitive restructuring, modification of patient's self-representations, and mindfulness (Frewen et al., 2008 ) can help in remediating the inefficiency of such a regulation, by modulating reaction to negative emotional stimuli (Fournier and Price, 2014 ). Specifically, research in mindfulness currently integrates theory and methods from eastern contemplative traditions, western psychology, and neuroscience and is based on neuroimaging techniques, physiological measures, and behavioral tests (Tang et al., 2015 ). In addition to this, complementary emotion-focused techniques, such as experiential focusing, systematic evocative unfolding, evocative experiential states, and relaxation techniques (e.g., diaphragmatic breathing and progressive muscle relaxation) can contribute to enhancing emotional soothing by a “bottom-up regulation” of the subcortical network, too (Faustino, 2022 ). In light of this, we highlight that a top-down and bottom-up integrated approach to the treatment of anxious or depressive symptoms is necessary to counteract the symptomatology reported by the patient. A very recent systematic review of fMRI studies examining the neural basis of CBT concluded that although anxiety and associated disorders are mediated by different neural circuitry, it can increase prefrontal control of subcortical structures (Brooks and Stein, 2022 ). In a pool of fMRI studies, it has also been reported that amygdala hyperactivation in PTSD is due to the ineffective inhibitory control by the medial prefrontal cortex (Stevens et al., 2013 ), while dysregulation in corticostriatal circuitry has been reported to describe the neuropathology of obsessive–compulsive and related disorders (Milad and Rauch, 2012 ).

With regard to the second approach, the use of neuroimaging to identify predictors of treatment outcomes in patients with psychiatric disorders has been rapidly increasing in the last few years (Weingarten and Strauman, 2015 ). Sectorial literature investigating predictive neuroimaging markers of psychotherapy response has specifically suggested that the anterior cingulate cortex, amygdala, and anterior insula emerged as potential markers in MDD and some anxiety disorders (Chakrabarty et al., 2016 ). Two resting-state PET studies found that CBT responders have lower pretreatment metabolic activity in the subgenual anterior cingulate cortex (Konarski et al., 2009 ; McGrath et al., 2013 ); a hypometabolism of the right anterior insula was also found as associated with the positive response to CBT (McGrath et al., 2013 ). Other resting-state functional studies showed an increased orbitofrontal cortex activity as associated with response to behavioral therapy in obsessive–compulsive disorder (Brody et al., 1998 ; Yamanishi et al., 2009 ). In a sample of patients with panic disorder, an improved response to exposure-based CBT was predicted by increased pretreatment activation in the bilateral insula and left dorsolateral prefrontal cortex during threat processing, as well as increased right hippocampal gray matter volume (Reineke, 2014 ). An fMRI study concluded that the excessive amygdala response to fear reflecting difficulties in managing anxiety reactions elicited during CBT might limit optimal response to therapy in PTSD (Bryant et al., 2008 ). Hyperactivity of higher-order visual areas as a reaction to emotional stimuli was associated with a response to CBT for social anxiety (Doehrmann et al., 2013 ; Klumpp et al., 2013 ). CBT response was also predicted by pretreatment activity in prefrontal regions and the amygdala in patients with a generalized social anxiety disorder (Klumpp et al., 2014 ). Recently, it has been reported that the resting-state pretreatment metabolic activity in the fronto-insular cortex may distinguish between patients likely to respond to psychotherapy, while high metabolic activity in the subgenual anterior cingulate cortex may be predictive of poor outcomes in MDD (Dunlop and Mayberg, 2014 ).

We conclude that research in brain imaging and psychotherapy may increase the availability of evidence-based standardized protocols for selected groups of patients affected by psychiatric disorders. Since psychotherapy requires a considerable amount of time and effort, having the means to foresee from the beginning whether a patient is likely to benefit from treatment could be of great clinical utility, and neuroimaging represents a promising method to this end. However, research in this area needs to acquire other evidence, and a certain amount of caution must be used with respect to the single patient application of brain imaging techniques which should be corroborated by comparison of altered neurophysiological patterns typically involved in the same clinical population.

• Neuroimaging techniques can be used to find biomarkers of brain functioning associated with psychotherapeutic treatment or to recognize outcome predictors;
• A neural circuitry of emotion dysregulation is associated with anxiety and depression symptoms, and psychotherapists should perform bottom-up and top-down regulation techniques to better control them;
• Research in brain imaging and psychotherapy may increase evidence-based standardized protocols for selected groups of psychiatric patients in order to augment treatment response and cost-effectiveness of health outcomes; and
• Technical and statistical limitations of integrating single-case (functional) neuroimaging and psychotherapy should be considered by therapists.

7. Interpersonal neurobiology perspective for somatic symptoms and related disorders

Various definitions, including “psychosomatic symptoms,” “functional symptoms,” “subjective health complaints,” “somatization,” “somatic symptom distress,” and “bodily distress,” have been used to depict a person's suffering related to physical symptoms (Van den Bergh et al., 2017 ). Diagnostic categories of Somatic Symptom Disorder (SSD) in the Diagnostic and Statistical Manual for Mental Disorders , fifth edition (DSM-5) (APA, 2013 ), Somatoform Disorders in the 10th Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) (World Health Organization, 2004 ) or Bodily Distress Disorder in the ICD-11 (WHO, 2019 ) are currently used in psychiatry nosography to classify the suffering of a person with a significant focus on physical symptoms such as pain, weakness, and breathlessness to a level that results in significant distress and functional limitation, low quality of life, work participation, and social interaction. Physical symptoms may or may not be associated with a diagnosed medical condition; however, the emphasis is on excessive thoughts, feelings, or behaviors related to their monitoring. Bodily distress is higher associated with depression and anxiety than specific medical conditions with comparable symptoms and well-defined organic pathology (e.g., IBS vs. inflammatory bowel disease, FMS vs. rheumatoid arthritis) (Henningsen, 2022 ). Moreover, individuals with somatic symptoms and related disorders experience difficulty in accepting that their concerns are excessive and prefer consulting general medical services rather than mental health services, which result in increased healthcare costs. A meta-analysis found that approximately 30% of patients in primary care settings fulfill the criteria for somatic symptoms disorder, and up to 50% of them present with at least one physical complaint (Haller et al., 2015 ).

Somatic symptoms and related disorders are challenging to treat for psychotherapists (Weigel et al., 2020 ). Because patients with somatic symptoms and related disorders are notably heterogeneous with respect to the nature and origins of their problems, the ability to design tailored interventions represents a central feature (Luyten and Fonagy, 2020 ). In the opinion of the authors, a neuroscience-based psychotherapy approach to such disorders should be performed within the framework of interpersonal neurobiology (IPNB), a scientifically grounded theory developed by Siegel ( 1999 ) as a field combining a wide array of science branches. The IPNB addresses three fundamental aspects of life, that is relationships (i.e., the sharing of energy and information flow), the brain (i.e., the embodied mechanisms of energy and information flow), and the mind (i.e., an emergent self-organizing activity of the brain regulating the flow of energy and information). Siegel stated that A healthy mind is a mind that creates integration within the body and its brain (…) (Siegel, 2019 , p. 229). “Integration” represents the basis of harmony in human beings and is essential for their health. The IPNB perspective supports the hypothesis that mental disorders are both an outcome of blocked integration and result in further impairments to integration (Siegel, 2012 ). The integration or linking of differentiated parts of a system can be seen as the fundamental process of wellbeing and appears to be at the core of emotional regulation. Neural integration, enabling differentiated areas to communicate effectively to be part of a functional whole, can promote emotional regulation (Siegel, 2019 ). To this end, the “vertical integration” invoked by the author (Siegel, 2006 ) includes body-proper sensations, brainstem, limbic circuits, and middle prefrontal cortex structures. In the opinion of the author, this can be particularly relevant for somatic symptoms and related disorders treatment in order to transform a disconnected way of living into a more integrated personal identity. We think that mindful awareness training as a form of internal attunement (Siegel, 2012 ) can constitute an example of an intervention from which such a kind of mental disorder may benefit. Reducing physiological arousal and interoceptive hypervigilance through relaxation and exploring emotional control, experiences, expectations, beliefs, and illness behavior, as well as correcting catastrophic misinterpretations of somatic sensations (Van den Bergh et al., 2017 ; Henningsen, 2022 ) during psychotherapeutic treatment can further enhance the vertical integration.

• The IPNB developed by Siegel ( 1999 ) may explain in more detail the need for integration between the body and the mind for subjective wellbeing;
• A “vertical integration” of body-proper sensations, brainstem, limbic circuits, and middle prefrontal cortex structures supported by specific techniques may aid the treatment of somatic symptoms and related disorders.

8. Discussion

According to previous attempts to point out neuroscience-based psychotherapy principles (Cappas et al., 2005 ; Faustino, 2021 ), the traditional dualism between brain and mind is no longer tenable. In the near future, we wish that neuroscience-based psychotherapy can contribute to the unification of its fragmented field, given that each specific school approach explains only 8% of the variance of the results and the most important common factor called into question to explain the patient's change after treatment is the therapeutic alliance (Wampold and Imel, 2015 ). Nearly 75% of patients commonly receiving psychotherapy improve after treatment compared to those who do not receive any treatment or ameliorate on their own (Jiménez et al., 2018 ). Moreover, psychotherapy—without difference in schools approach—is comparable in effectiveness to medication and has no relevant side effects (Leichsenring et al., 2022 ).

Memory is a fundamental trait of adaptive behavior, and it is never the same as itself. Starting from studies exploring molecular and cellular mechanisms underlying long-term memory formation and reconsolidation, psychotherapists should be fully aware of the crucial role they have in redesigning the patients' narrative plot, with a significant impact on identity and psychopathological symptoms relief. The investigations in which biological markers have found their way into psychotherapy research are still rare to date. We think that this represents a promising area to be implemented in the near future, bypassing potential methodological limitations (Piotrkowicz et al., 2021 ) as in the case of BDNF detection that should be added as a supplement to symptom scales commonly used to analyze psychotherapeutic effects. Since their potential to provide information about a therapeutic alliance that cannot be only derived from self-report questionnaires, salivary oxytocin/cortisol should be collected repeatedly during the treatment course from both patient and therapist before the therapeutic session, in order to collect biological data able to better describe the special bond between patient and therapist.

As people use their cognitive abilities to engage in everyday life, cognitive psychopathology has to be considered a crucial aspect of individuals adhering to psychotherapy. Many psychiatric disorders include the disruption of some aspects of cognition, and these deficits may predispose individuals to psychopathology, constitute an early marker, sustain the disorder, and predict the likelihood of functional recovery and successful rehabilitation. As a result, cognition and associated neural circuitry should be recognized as a key target of treatment by psychotherapists.

According to Bonini et al. ( 2022 ), studies of mirror mechanisms will lead to new research avenues in neuropsychiatric conditions in the near future. We are also confident in the increasing use of neuroimaging techniques to refine our understanding of both the outcome and process of psychotherapy, inform practitioners about evidence-based methods for specific psychiatric disorders, and help researchers to better define treatment protocols. In the opinion of the authors, an in-depth study of the implications of the dopaminergic mesocorticolimbic system of patients is really promising, with the aim of depicting the process of motivation to change as an intrinsic lever of the psychotherapeutic process. To this end, we think that brain imaging can play a relevant role, too.

Professionals must have timely access to information for optimal care implementation and a promising area of research based on advancements in MRI techniques (e.g., diffusion tensor imaging, DTI; BOLD fMRI signals from different brain regions) referred to the “connectome,” will permit researchers to shift attention from discrete brain areas to networks of brain regions supporting psychological dysfunction (Weingarten and Strauman, 2015 ). Systematic validation of biomarkers for independent clinical populations and integration with clinical data can augment their value for predicting psychotherapy outcomes. However, initial neuroimaging findings should be replicated in larger clinical populations and across a range of psychiatric disorders avoiding clinical decision-making on single cases due to the person's complexity (e.g., the potential presence of comorbidity) and limited generalizability of results.

Finally, we want to point out that by a neuroscience-based view of psychotherapy, the brain should be properly recognized as an interpersonal and a historical organ along the drawn lines of social neuroscience or neurophenomenology (cf., Varela, 1996 ; Cacioppo et al., 2002 ; Fuchs, 2003 ). This can stem a potential drift toward a more accurate knowledge of somatization and mind–body connection.

9. Conclusion

We have explored several paths regarding the neurobiological mechanisms through which psychological changes occur to sustain the future development of psychotherapy based on brain functioning and modeling. The latest discoveries in the neuroscientific field have shed light on the means by which psychotherapy proves to be a successful practice. For its part, psychotherapy can contribute to neuroscience by making available data from an accurate clinical activity that links the semeiotic investigation to the uniqueness of the patient and that bases its workout on the relational dimension of change, i.e., the therapeutic relationship. We also speculate that a neuroscience-based approach can really change and ameliorate our current psychotherapeutic interventions starting immediately by integrating in clinical practice patients' evaluation of cognitive domains mainly involved in the manifested mental disorder, top-down regulation techniques over the limbic system (i.e., emotions labeling, problem-solving, cognitive reappraisal, cognitive restructuring, mindfulness, and modification of patients' self-representations) and bottom-up interventions addressing somatosensory features of unresolved trauma (cf., Odgen et al., 2006 ) as well as “memory therapeutics” (i.e., accelerated resolution therapy, rewind techniques, cognitive restructuring, and imagery modification) able to redesign the narrative plot and the person's sense of the Self. Such improvements can be finalized after training of practitioners where necessary. Finally, according to a previous review suggesting that psychotherapy can influence the brain and behavior through the adaption of gene expression to the environment (Jiménez et al., 2018 ), we endorse the increasing consensus that it entails new learning in the context of an emotional relationship leading to epigenetic modifications after treatment.

Author contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Acknowledgments

The first author gratefully acknowledges Gabriele Cammisuli for his inexhaustible source of love and inspiration that allows him to integrate paternity and his work as a researcher.

Funding Statement

This research received funding from the Italian Ministry of Health.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Guessing game: Response may bias understanding of future scenarios

Findings could aid research into how information presentation might prevent human error.

Does previous experience bias a person in future estimations? Yes, Osaka Metropolitan University researchers in Japan report, but only if the person engages higher processing powers by responding, as opposed to simply observing.

They made their findings through experiments involving participants estimating the number of dots flashed on a screen. Participants either had to input their estimate before making another estimate on a new set of dots or were not prompted to do anything but observe. The researchers found that those asked to respond demonstrated serial dependence.

"What we see or hear is influenced by what we saw or heard before," said Professor Shogo Makioka at the Graduate School of Sustainable System Sciences, Osaka Metropolitan University. "The way we are influenced depends on the stimulus and time interval. If we are influenced toward what came before, meaning we are biased toward believing that separate items are more similar, we call that serial dependence."

The findings were published on January 24, 2024, in Scientific Reports .

In the first experiment in this paper, 35 participants were shown dots for a quarter of a second then prompted to provide their estimated answer for the number before being shown another set of dots. Later, the same participants were shown dots but not prompted to provide an answer, before being shown another set of dots and again prompted to estimate.

In the second experiment, 23 participants were prompted for an answer at random. The researchers found that participants who were prompted to respond were more likely to provide an answer closer to their most recent observation.

"The experiments demonstrated that the influence of serial dependence is stronger immediately after a response is requested," said co-author Yukihiro Morimoto, a third-year doctoral student at the university. "This is an important finding when considering how to present information to prevent human error."

The researchers noted, however, they did not find a correlation between serial dependence and accuracy, likely because the number of dots were random, rather than in intentional groupings or patterns.

According to Professor Makioka, stronger serial dependence following response is due to the higher processing the participant must use to observe and estimate the number of dots, then translate that into an answer.

"We are now investigating whether serial dependence related to numbers also occurs in children and whether it occurs when numbers are presented through sound," Professor Makioka said. "Through these studies, we aim to provide clearer guidelines for preventing human error by uncovering, in detail, the ways in which serial dependence arises and how number-related processes work."

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Journal Reference :

• Yukihiro Morimoto, Shogo Makioka. Response boosts serial dependence in the numerosity estimation task . Scientific Reports , 2024; 14 (1) DOI: 10.1038/s41598-024-52470-0

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Pbs graduate student miriam janssen's paper receives d.g. marquis behavioral neuroscience award, posted on march 12, 2024 by lisa d. aubrey.

Graduate student Miriam Janssen's paper, "The Motivational Role of the Ventral Striatum and Amygdala in Learning From Gains and Losses," was awarded the 2023 D.G. Marquis Behavioral Neuroscience Award . This award is given each year to recognize the best paper published in Behavioral Neuroscience .

Miriam is a second-year student in the van der Meer Lab.

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Collection  12 March 2023

Top 100 in Neuroscience - 2022

This collection highlights our most downloaded* neuroscience papers published in 2022. Featuring authors from around the world, these papers showcase valuable research from an international community.

You can also view the top papers across various subject areas here .

*Data obtained from SN Insights, which is based on Digital Science's Dimensions.

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Reduced variability of bursting activity during working memory

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Changes in the excitability of primary hippocampal neurons following exposure to 3.0 GHz radiofrequency electromagnetic fields

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A psychophysical and neuroimaging analysis of genital hedonic sensation in men

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Bupivacaine reduces GlyT1 expression by potentiating the p-AMPKα/BDNF signalling pathway in spinal astrocytes of rats

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Prolonged and extended impacts of SARS-CoV-2 on the olfactory neurocircuit

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GABAergic CA1 neurons are more stable following context changes than glutamatergic cells

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Behavioral and inflammatory sex differences revealed by celecoxib nanotherapeutic treatment of peripheral neuroinflammation

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Distinct spatio-temporal and spectral brain patterns for different thermal stimuli perception

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Astrocyte-secreted chordin-like 1 regulates spine density after ischemic injury

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Brain structural and functional correlates to defense-related inhibition of muscle sympathetic nerve activity in man

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Opto-electrical bimodal recording of neural activity in awake head-restrained mice

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Prefrontal projections to the nucleus reuniens signal behavioral relevance of stimuli during associative learning

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Long-lasting reflexive and nonreflexive pain responses in two mouse models of fibromyalgia-like condition

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Sexually dimorphic peripheral sensory neurons regulate copulation duration and persistence in male Drosophila

• Shreyas Jois
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An almost nontoxic tetrodotoxin analog, 5,6,11-trideoxytetrodotoxin, as an odorant for the grass puffer

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Neuronal modulation in the mouse superior colliculus during covert visual selective attention

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An assessment of the rescue action of resveratrol in parkin loss of function-induced oxidative stress in Drosophila melanogaster

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Wnt/β-catenin signaling promotes neurogenesis in the diencephalospinal dopaminergic system of embryonic zebrafish

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The effects of locomotion on sensory-evoked haemodynamic responses in the cortex of awake mice

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Ultrafast Doppler imaging and ultrasound localization microscopy reveal the complexity of vascular rearrangement in chronic spinal lesion

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Ultrasound stimulation improves inflammatory resolution, neuroprotection, and functional recovery after spinal cord injury

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Symptom-based pharmacotherapy for neuropathic pain related to spinal disorders: results from a patient-based assessment

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The role of the meningeal lymphatic system in local meningeal inflammation and trigeminal nociception

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Dietary restriction ameliorates TBI-induced phenotypes in Drosophila melanogaster

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Odor blocking of stress hormone responses

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• Luis R. Saraiva
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Adenosine A 2A receptors control synaptic remodeling in the adult brain

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The transcription factor unc-130 / FOXD3/4 contributes to the biphasic calcium response required to optimize avoidance behavior

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Imaging peripheral nerve micro-anatomy with MUSE, 2D and 3D approaches

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The impact of pitolisant, an H 3 receptor antagonist/inverse agonist, on perirhinal cortex activity in individual neuron and neuronal population levels

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The importance of self-efficacy and negative affect for neurofeedback success for central neuropathic pain after a spinal cord injury

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Disentangling the critical signatures of neural activity

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Neurons in the pigeon visual network discriminate between faces, scrambled faces, and sine grating images

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Novel adult cortical neuron processing and screening method illustrates sex- and age-dependent effects of pharmaceutical compounds

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Characterization of somatosensory neuron involvement in the SOD1 G93A mouse model

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Viral strategies for targeting spinal neuronal subtypes in adult wild-type rodents

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Altered activity of pain processing brain regions in association with hip osteoarthritis

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Activation of the Hepcidin-Ferroportin1 pathway in the brain and astrocytic–neuronal crosstalk to counteract iron dyshomeostasis during aging

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Dynamics of phase oscillator networks with synaptic weight and structural plasticity

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Oxytocin via oxytocin receptor excites neurons in the endopiriform nucleus of juvenile mice

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Stria medullaris innervation follows the transcriptomic division of the habenula

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Super-resolved fluorescence imaging of peripheral nerve

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Internal state affects local neuron function in an early sensory processing center to shape olfactory behavior in Drosophila larvae

• Seth R. Odell
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Drosophila septin interacting protein 1 regulates neurogenesis in the early developing larval brain

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Contextual memory reactivation modulates Ca 2+ -activity network state in a mushroom body-like center of the crab N. granulata

• Francisco Javier Maza
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Bursting of excitatory cells is linked to interictal epileptic discharge generation in humans

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Improvement of the affinity of an anti-rat P2X4 receptor antibody by introducing electrostatic interactions

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A glibenclamide-sensitive TRPM4-mediated component of CA1 excitatory postsynaptic potentials appears in experimental autoimmune encephalomyelitis

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Oral cancer induced TRPV1 sensitization is mediated by PAR 2 signaling in primary afferent neurons innervating the cancer microenvironment

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Vagus nerve stimulation does not improve recovery of forelimb motor or somatosensory function in a model of neuropathic pain

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Novel roles of phentolamine in protecting axon myelination, muscle atrophy, and functional recovery following nerve injury

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Low frequency visual stimulation enhances slow wave activity without disrupting the sleep pattern in mice

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Neuromodulator-dependent synaptic tagging and capture retroactively controls neural coding in spiking neural networks

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Neural signature of the perceptual decision in the neural population responses of the inferior temporal cortex

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Functional connectivity response to acute pain assessed by fNIRS is associated with BDNF genotype in fibromyalgia: an exploratory study

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All-optical manipulation of the Drosophila olfactory system

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Identifying long-range synaptic inputs using genetically encoded labels and volume electron microscopy

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Neuroprotective effects of violacein in a model of inherited amyotrophic lateral sclerosis

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A miniature fluorescence microscope for multi-plane imaging

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Expression of antioxidant enzymes in lesions of multiple sclerosis and its models

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Passage number affects differentiation of sensory neurons from human induced pluripotent stem cells

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The dynamics of protein localisation to restricted zones within Drosophila mechanosensory cilia

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Integrative multiomic analyses of dorsal root ganglia in diabetic neuropathic pain using proteomics, phospho-proteomics, and metabolomics

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Blast-induced axonal degeneration in the rat cerebellum in the absence of head movement

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Cellular mechanisms underlying state-dependent neural inhibition with magnetic stimulation

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Peripheral N -methyl- d -aspartate receptor activation contributes to monosodium glutamate-induced headache but not nausea behaviours in rats

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Ferroptosis inhibition by deferiprone, attenuates myelin damage and promotes neuroprotection in demyelinated optic nerve

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Conditioned up and down modulations of short latency gamma band oscillations in visual cortex during fear learning in humans

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Spontaneous activity in whisker-innervating region of neonatal mouse trigeminal ganglion

• Piu Banerjee
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Public Health

'all of us' research project diversifies the storehouse of genetic knowledge.

Results from a DNA sequencer used in the Human Genome Project. National Human Genome Research Institute hide caption

Results from a DNA sequencer used in the Human Genome Project.

A big federal research project aimed at reducing racial disparities in genetic research has unveiled the program's first major trove of results.

"This is a huge deal," says Dr. Joshua Denny , who runs the All of Us program at the National Institutes of Health. "The sheer quantify of genetic data in a really diverse population for the first time creates a powerful foundation for researchers to make discoveries that will be relevant to everyone."

The goal of the $3.1 billion program is to solve a long-standing problem in genetic research: Most of the people who donate their DNA to help find better genetic tests and precision drugs are white.

"Most research has not been representative of our country or the world," Denny says. "Most research has focused on people of European genetic ancestry or would be self-identified as white. And that means there's a real inequity in past research."

For example, researchers "don't understand how drugs work well in certain populations. We don't understand the causes of disease for many people," Denny says. "Our project is to really correct some of those past inequities so we can really understand how we can improve health for everyone."

But the project has also stirred up debate about whether the program is perpetuating misconceptions about the importance of genetics in health and the validity of race as a biological category.

New genetic variations discovered

Ultimately, the project aims to collect detailed health information from more than 1 million people in the U.S., including samples of their DNA.

In a series of papers published in February in the journals Nature , Nature Medicine , and Communications Biology , the program released the genetic sequences from 245,000 volunteers and some analysis of those data.

"What's really exciting about this is that nearly half of those participants are of diverse race or ethnicity," Denny says, adding that researchers found a wealth of genetic diversity.

"We found more than a billion genetic points of variation in those genomes; 275 million variants that we found have never been seen before," Denny says.

"Most of that variation won't have an impact on health. But some of it will. And we will have the power to start uncovering those differences about health that will be relevant really maybe for the first time to all populations," he says, including new genetic variations that play a role in the risk for diabetes .

Shots - Health News

Researchers gather health data for 'all of us'.

But one concern is that this kind of research may contribute to a misleading idea that genetics is a major factor — maybe even the most important factor — in health, critics say.

"Any effort to combat inequality and health disparities in society, I think, is a good one," says James Tabery , a bioethicist at the University of Utah. "But when we're talking about health disparities — whether it's black babies at two or more times the risk of infant mortality than white babies, or sky-high rates of diabetes in indigenous communities, higher rates of asthma in Hispanic communities — we know where the causes of those problem are. And those are in our environment, not in our genomes."

Race is a social construct, not a genetic one

Some also worry that instead of helping alleviate racial and ethnic disparities, the project could backfire — by inadvertently reinforcing the false idea that racial differences are based on genetics. In fact, race is a social category, not a biological one.

"If you put forward the idea that different racial groups need their own genetics projects in order to understand their biology you've basically accepted one of the tenants of scientific racism — that races are sufficiently genetically distinct from each other as to be distinct biological entities," says Michael Eisen , a professor of molecular and cell biology at the University of California, Berkeley. "The project itself is, I think, unintentionally but nonetheless really bolstering one of the false tenants of scientific racism."

While Nathaniel Comfort, a medical historian at Johns Hopkins, supports the All of Us program, he also worries it could give misconceptions about genetic differences between races "the cultural authority of science."

Denny disputes those criticisms. He notes the program is collecting detailed non-genetic data too.

"It really is about lifestyle, the environment, and behaviors, as well as genetics," Denny says. "It's about ZIP code and genetic code — and all the factors that go in between."

And while genes don't explain all health problems, genetic variations associated with a person's race can play an important role worth exploring equally, he says.

"Having diverse population is really important because genetic variations do differ by population," Denny says. "If we don't look at everyone, we won't understand how to treat well any individual in front of us."

• diversity in medicine
• human genome
• genetic research

WVU neuroscience students pioneer new frontiers in undergraduate research

Posted on March 11, 2024

As Jayla Boyd and Lillian Floyd would describe it, they were in uncharted territory when they arrived on the West Virginia University campus for Brain Camp . By the end of the week, the soon-to-be high school seniors had discovered the complex world of neuroscience and were hooked.

“I had an interest in medicine from the start, but Brain Camp was my first taste of neuroscience,” Jayla said. “It gave me an opportunity to explore something I wasn't being taught in high school. I instantly fell in love.”

The two students learned about Nelson’s research related to circadian rhythms during Brain Camp. The session sparked an interest for Jayla who worked with the Research Apprenticeship Program once she became a WVU student to be placed in his lab, and Lillian joined her after reaching out to Nelson about research opportunities.

Jayla is contributing to a study investigating optimal times for chemotherapy administration based on circadian rhythms and permeability of the blood-brain barrier, which keeps foreign substances from entering the brain and limits potentially effective medicines, immunotherapy, gene therapy and other therapeutics. Using the natural increase of permeability, which changes throughout the course of the day, may assist with delivering drugs into the brain more effectively.

Lillian’s research is focused on ghrelin, a hormone associated with hunger, and its impacts on tumor cell growth and breast cancer. The study is expanding on prior research by investigating additional genes associated with tumor growth and metastasis into the brain conducted by William Walker , a postdoctoral researcher in the lab.

“I believe strongly that allowing opportunities for undergraduates to learn about and participate in research is critical for their education,” Nelson said. “One of my favorite things about being on the WVU faculty is hosting undergraduate students to conduct meaningful research in our lab. Virtually every faculty member I know, including me, had the wonderful opportunity to participate in research as undergraduate students, an experience that shaped our understanding of how information and knowledge are generated and adjusted over time, and motivated many of us to pursue a career in science.”

“Participating in research has allowed me to improve my classroom academics, and the classroom academics help me improve my research,” Jayla said. “It’s a back-and-forth relationship that has made me think and grow.”

Lillian echoed Jayla’s thoughts, adding that in-class lessons have added to the research experience and provided insights into a future career.

“It’s helpful that in class we’re learning the foundations for what we’re doing in the lab,” Lillian said. “We’re immediately applying all our knowledge, which makes it that much more well-rounded.

“It has given me a step ahead in seeing what research as a career is like, what people do in their day-to-day, and it’s something you can’t get in the classroom. It has helped with determining what I want to do as a career.”

Looking toward the future, Jayla and Lillian are unsure exactly what path they want to pursue after earning a bachelor’s degree but are thankful for the opportunities research has provided them so far to learn more about the field of neuroscience and fulfill their purpose.

“I love it. I definitely want research to be a part of my future,” Jayla said. “I'm not sure whether I will choose a path in medicine or a path in only research, but I definitely want that to be a part of my future.”

Lillian is considering similar paths as her academic journey continues.

“I know that I'm really interested in helping people, whether that's through researching and figuring out solutions to problems or becoming a medical doctor and diagnosing and treating people,” Lillian said. “I'm not sure where or what I will be doing, but the ultimate goal remains the same. I want to help people and solve problems.”

To future college students, they both recommend participating in a camp experience to discover new interests and careers, and they credit Brain Camp with helping guide their path forward.

“I was born a Mountaineer,” said Jayla, of Charleston, whose father and grandparents are WVU alumni. “When I decided to go to college, of course WVU was on my list, but I didn’t understand why it was so important to my family.

“I had so many lists and spreadsheets trying to determine what would be the best place for me, but sometimes you just know, and that’s how I felt when I came here. I just felt comfortable. I felt like I could be myself, and I felt a sense of peace at WVU compared to other campuses. The academics were incredible. The people around me were so knowledgeable. Without Brain Camp, I wouldn't have had the chance to experience the day-to-day life of a student.”

The annual camp, hosted by the School of Medicine Department of Neuroscience and Rockefeller Neuroscience Institute , offers high school juniors and seniors a week of exploration, discovery and hands-on activities led by expert neuroscience faculty and graduate students.

Lillian, from Parkersburg, had a similar experience. She knew a lot of individuals who graduated from the University and was familiar with the innovative research into memory health , such as Alzheimer’s disease, being conducted at the Rockefeller Neuroscience Institute, but it wasn’t until Brain Camp that her decision to pursue a degree in the field was solidified.

“Learning about how we learn, learning about how our mind works is kind of incredible,” Lillian said. “Neuroscience feels like a whole new uncharted territory, which I think is incredible.

“Brain Camp gave us an inside look. It was really interesting to be able to see what was going on, who were the people doing research, how was it happening. I was thrilled with everything.”

The experience also provided the opportunity to build relationships with future classmates, making the transition to college life easier.

“There was a lot of bonding,” Lillian recalled. “We all stayed in the Oakland dorm, all went to the Towers to eat our breakfast and lunch and trekked up the Health Sciences hill together. We also had a group chat where everyone said, I'm going to WVU. So, it was exciting to see someone that you knew in your classes.”

As they reflect on the experience, they say future students should keep an open mind and pursue opportunities to learn something new.

“I would really recommend one of the camps,” Lillian said of the variety of opportunities she saw on campus. “While we were at Brain Camp, there were so many other students who were here for mineral resources, engineering, environmental. It was interesting to see everyone that was pursuing their passions and seeing what was going on at West Virginia University.”

“I would tell someone to explore, just try new things,” Jayla said. “I didn’t know anything about neuroscience coming into Brain Camp, and I left knowing what I wanted to do with my life.”

Photo at Top: Jayla Boyd (left) and Lillian Floyd (right) were in uncharted territory when they arrived on the WVU campus for Brain Camp the summer before their senior year of high school. Now, the students are enrolled as freshman in the neuroscience program and are conducting research in the School of Medicine. (WVU Photo/Davidson Chan)

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MEDIA CONTACT: Jessica Wilmoth Senior Communications Specialist University Relations — Health Sciences

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