Abstract
Major depressive disorder (MDD) is a highly heterogeneous mental disorder, and its complex etiology and unclear mechanism are great obstacles to the diagnosis and treatment of the disease. Studies have shown that abnormal functions of the visual cortex have been reported in MDD patients, and the actions of several antidepressants coincide with improvements in the structure and synaptic functions of the visual cortex. In this review, we critically evaluate current evidence showing the involvement of the malfunctioning visual cortex in the pathophysiology and therapeutic process of depression. In addition, we discuss the molecular mechanisms of visual cortex dysfunction that may underlie the pathogenesis of MDD. Although the precise roles of visual cortex abnormalities in MDD remain uncertain, this undervalued brain region may become a novel area for the treatment of depressed patients.
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Introduction
Major depressive disorder (MDD) is the most common serious mental illness. According to the World Health Organization statistics, MDD will rank first in the global human disease burden in 2030 [1], and one-third of the annual global suicides are related to MDD [2]. In particular, the COVID-19 pandemic triggered a 28% increase in the prevalence of MDD globally [3].
The core brain regions associated with emotional disorders include the hippocampus, prefrontal lobe, amygdala, hypothalamus, and habenula [4, 5]. However, increasing evidence also shows that the visual cortex is associated with depression and antidepressant efficacy. In this manuscript, we review the research progress on visual cortex dysfunctions in patients with depression and animal models, based on different techniques and their correlation with depression and antidepressant efficacy. Through analyzing these research findings, we hope to present a new perspective on the role of the visual cortex in the occurrence and development of depression and antidepressant treatments.
Clinical Neuroimaging Studies of Visual Cortical Structure and Function in MDD
Neuroimaging is a helpful non-invasive tool with which to investigate mechanisms underlying depression. It provides anatomical and physiological information through structural imaging and functional imaging [6]. Combining the static and dynamic information from these imaging studies can help to understand the complex pathophysiology of MDD (Fig. 1).
Neuroimaging studies of visual cortical structure and function in depressed patients. The changes in the visual cortex in depressed patients are observed through structural and functional imaging. Red upward arrows indicate an increase; red downward arrows indicate a decrease. BLA, basolateral amygdala; CBF, cerebral blood flow; DC, degree centrality; FC, functional connectivity; GMV, grey matter volume; OB, occipital bending; rs-fMRI, resting-state functional magnetic resonance imaging; sMRI, structural magnetic resonance imaging; t-fMRI, task-related functional magnetic resonance imaging; V1, primary visual cortex.
Structural Imaging of the Visual Cortex
As early as 2004, Sanacora et al. found that the grey matter volume (GMV) of the occipital lobe of MDD patients was significantly increased, while the total volume and white matter volume of the occipital lobe were significantly reduced compared with healthy controls (HCs) in a small sample as measured by structural magnetic resonance imaging (sMRI) [7]. An independent large sample sMRI study further found that the occipital cortex GMV of lifelong MDD patients is abnormally increased compared with non-lifelong MDD patients [8]. Support vector machine classifier analysis of sMRI data showed increased GMV in the bilateral superior marginal gyrus and occipital lobe of MDD patients, whereas increased GMV was found in the right dorsolateral prefrontal lobe of bipolar disorder (BD) patients. These structural differences can distinguish MDD and BD at the individual level with 75% accuracy [9]. However, a study found that young people who often witnessed domestic violence in childhood, as a high-risk group for depression, have decreased GMV and thickness of the visual cortex in adulthood, the bilateral secondary visual cortex and the left occipital pole being the most strongly affected [10].
An association study between patients with recurrent MDD and HCs showed that single nucleotide polymorphisms (SNPs) of two thyroid hormone transporter genes, rs496549, and rs479640, are associated with GMV in the left occipital cortex [11]. The Shanghai Mental Health Center analyzed the interaction of the tumor necrosis factor-α SNP, rs1799724, with voxel-based morphometry and structural covariance-based graph theory in 144 MDD patients and 111 HCs, and found that the interaction of rs1799724 is only localized to the visual cortex (right superior occipital gyrus), and the visual cortex volume of MDD patients is smaller than that of HCs [12]. An analysis of the transcriptome-based polygenic risk score (T-PRS) from a non-clinical sample of young adults with MDD and the Psychiatric Genomics Consortium-MDD genome-wide association analysis database demonstrated that T-PRS is associated with the severity of depression and hypergyrification in the temporal and occipital lobes of male MDD patients [13].
Occipital bending (OB) is an asymmetrical development of the occipital lobe where one lobe crosses the midline of the brain and wraps around the other lobe. This condition is three times more common in MDD patients than HCs and right OB is strongly correlated with major depression. MDD patients with right OB have a greater cortical thickness in three areas of the left occipital lobe (cuneus, lingual gyrus, and calcarine sulcus) and a 20% reduction in the size of the bilateral lateral ventricles [14]. Taken together, these cortical structural differences, including GMV and OB, may suggest maladaptive visual cortical plasticity changes relating to depression.
Function Imaging of the Visual Cortex
Resting-State Functional Magnetic Resonance Imaging (rs-fMRI)
Comparison of the degree centrality (DC) in 10 different frequency subbands in the rs-fMRI blood oxygenation level-dependent (BOLD) fluctuation data showed that there are frequency-specific changes in the occipital lobe of MDD patients. The decreased DC in MDD patients is mainly concentrated in the occipital lobe in the low-frequency band [15]. The visual cortex can be divided into the ventral pathway for sensing shapes and the dorsal pathway for sensing spatial position [16]. In MDD patients, the dorsal visual pathway, involved in visuospatial processing, and the anterior/posterior parts of the right temporoparietal junction, involved in cognitive, emotional, and social processes, show interrupted resting-state functional connectivity [17]. Multivariable distance correlation between the dorsal attention network and the dorsal/ventral visual network was applied to quantify the connectivity between the networks in 86 drug-naive MDD patients and 73 HCs. It was found that the autonomy of the dorsal/ventral visual network in MDD patients was enhanced, that is a better, more economical, and efficient organization with enhanced independence and less external regulation by the attention network. These results showed functional dysconnectivity of the visual network in MDD patients that suggested a pathogenic role of visual systems [18].
A study based on rs-fMRI showed abnormal connections within and between the visual and auditory networks of MDD patients. The connectivity of the auditory networks, and visual components 2 (VC2) and 3 (VC3) in MDD patients are reduced. The connection between the auditory network and VC3 is weakened and the abnormal functional connectivity (FC) in the visual network is related to the clinical symptoms of MDD [19]. Depression in old age includes early-onset depression (EOD) and late-onset depression (LOD). Although the clinical symptoms of both are similar, the potential mechanism, treatment strategy, and clinical prognosis are different [20]. In a study evaluating the memory, executive function, and processing speed of 82 late-life depression (LLD) patients (40 EOD and 42 LOD patients) and 90 HCs, rs-fMRI, and Granger causality analysis found that the functional modularity and division are different for EOD and LOD patients, and the dorsal visual cortex region of interest is a potential specific node in module allocation [21].
MDD and post-traumatic stress disorder (PTSD) are highly comorbid [22], and up to 50% of PTSD patients are also diagnosed with MDD [23]. A study conducted interviews, symptom measurements, and rs-fMRI on 38 veterans who met the diagnostic criteria of depression/PTSD comorbidity. It was found that the FC between the left basolateral amygdala (BLA) and the primary visual cortex (V1) was increased in female patients, while the severity of depressive symptoms in men was related to an increased FC between the left BLA and bilateral occipital lobes [24].
Task-Related fMRI (t-fMRI)
Non-emotion Related Visual Tasks
Task-based functional MRI in response to visual stimuli has been applied extensively in patients with MDD. An fMRI study revealed that MDD patients show abnormal filtering of irrelevant information in the visual cortex and abnormal changes in the FC between the frontoparietal network and the visual cortex [25]. Other mental disorders are usually accompanied by depressive symptoms. In a study of schizophrenic patients, no significant activation of the middle occipital gyrus (MOG) was observed when they performed object perception-related tasks during fMRI, while both sides of the MOG were significantly activated in HCs. Depressive symptoms were significantly associated with increased activation of the right MOG, while anxiety was significantly associated with decreased activation [26]. BD usually alternates between depression and mania. The fMRI data showed that the visual cortical responses of patients in the depressive and manic states were reduced compared with patients in the healthy state and HCs, suggesting that abnormal visual processing may be one of the characteristics of BD [27].
Visual Perception Changes
A psychophysical visual motor processing task-based study showed that MDD patients have enhanced motor awareness of typical inhibitory stimuli compared with a control group, and the degree of spatial inhibition is related to the individual disease load [28]. The decline in spatial inhibition still exists after the patient has stopped medication for several months following clinical rehabilitation, indicating that the spatial inhibition of visual pathways may be a consequence of MDD and may last for a long time. This MDD-specific performance is related to stimulus characteristics (such as contrast, size, and presentation time) and is the result of changes in early visual processing rather than general defects or cognitive biases [28]. A recent study evaluated the motor visual perception of MDD patients by analyzing the results of their judgment of the direction of motion stimulated by a moving grating. The results showed that MDD patients took longer to make a correct judgment, and the weaker the peripheral inhibition ability, the more severe the depression, which was manifested as a higher Hamilton depression score. This study suggested that MDD patients’ ability to follow movements in the external world is significantly weakened [29]. Moreover, transcranial direct current stimulation (tDCS) of MDD patients receiving a single stimulation of the left dorsolateral prefrontal cortex (DLPFC) can also reverse the selective impairment of visual processing speed in these patients [30]. tDCS can stimulate the bilateral occipital lobe to induce long-term potentiation-like plasticity of the occipital lobe in HCs, which may be an important mechanism by which tDCS restores synaptic plasticity disorders of mental diseases, such as depression and schizophrenia [31].
Emotion-related Visual Tasks
Attention Bias: Anxious individuals show a “vigilance-avoidance” pattern of attention towards threatening stimuli when both threatening and neutral stimuli are presented simultaneously, a phenomenon called “threat bias” [32]. A study by Barch’s group screened 25 adolescents with and 27 without “threat avoidance” using a point detection task, and assessed brain responses to threatening and neutral faces by fMRI [33]. The results showed that the activity of several regions involved in early visual and face processing in the occipital, parietal, and temporal lobes is lower when adolescents with “threat avoidance” are presented with threatening and neutral faces [33]. Importantly, adolescents with a history of depression and/or anxiety exhibit reduced activity in these three brain regions regardless of the type of face presented. This study suggests that using attention training to change threat bias during adolescence may reduce anxiety/depression symptoms [33]. An emotional interference task-based fMRI study revealed that MDD adolescents show greater activation in the frontal cingulate gyrus and parietal occipital region when ignoring fear faces and neutral faces, that is, they need greater brain activation in cognitive control and visual attention. The authors suggested that attention bias towards negative emotions is one of the important characteristics of adolescent MDD [34]. In addition, a continuous attention task-based fMRI study showed that the activation of the occipital lobe decreases in adolescent MDD patients in the absence of reward [35]. Both adolescent and adult MDD patients have an impaired ability to selectively pay attention to negative emotions and inhibit negative stimuli. An emotional Go/No-Go task-based fMRI study reported that MDD adolescents have a decreased BOLD response in the right DLPFC and bilateral occipital lobe when “No-Go” targets and sad faces are presented, suggesting selective attention toward negative emotions and a reduced ability to suppress negative stimuli [36].
Impairments in Emotional Processing: The V1 region of MDD patients responds more strongly to emotional stimuli (happiness or sadness) than neutral stimuli [37] and the response of the right visual cortex to sadness predicts a good therapeutic effect of antidepressants [38]. A 7.0 T fMRI study showed no significant connection between V1 and the orbitofrontal cortex (OFC) in drug-naive female MDD patients, but significant positive regulation of the OFC-V1 pathway in HCs during a negative and neutral emotion image-viewing task, supporting the view that interruption of the effective connection between OFC and V1 may be closely related to the impairment of negative emotion processing and regulation in female MDD patients [39]. When MDD patients and HCs perform emotion regulation tasks, fMRI shows that the activity of the right amygdala and visual cortex in HCs are downregulated in negative emotional states, suggesting that there are obstacles in emotion regulation of the visual cortex in MDD patients [40].
By analyzing the activity pattern of the visual association area, the FC between the visual association area and prefrontal cortex, and the relationship between the visual association area and core clinical symptoms, a visual delayed recognition t-fMRI study revealed that MDD patients have connectivity interruption in the process of visual working memory updating, which is related to the retention of unrelated negative information, and could lead to persistent emotional abnormalities [41]. MDD patients show an overall decrease in the accuracy of performing emotional conflict tasks and reduced BOLD activity in the occipital region, which is responsible for face perception and emotional information processing. However, there is no difference in the response to fearful and happy faces [42]. Using alternating emotional and neutral visual stimuli, an fMRI study showed activation of the bilateral visual cortex during negative and neutral stimulation, but patients show stronger activation of the visual cortex and weaker activation of the left prefrontal cortex [43]. Patients with MDD and borderline personality disorder (BPD) differ in emotional regulation but are highly comorbid. A study that monitored HCs, MDD patients, and BPD/MDD comorbid patients by fMRI during emotional interference tasks showed that the visual cortex of BPD/MDD comorbid patients is more active during the activity [44]. However, additional studies are required to reveal the malleability of these structural correlates of attentional bias and emotional processing impairments and to determine whether this malleability is altered in patients suffering from depression. Together, these results may suggest maladaptive changes in visual cortical network plasticity that contribute to, and/or result from, depression.
The response of the right visual cortex to sadness stimuli predicts good therapeutic effects of antidepressants in MDD patients. A facial stimuli-task fMRI study showed that the severity of depression is positively correlated with the response of the right visual cortex to sad stimuli and negatively correlated with the response of the left visual cortex to happy stimuli in the early stage of treatment. After treatment, a decrease in the response of the right V1 to sad rather than happy stimuli is associated with a decrease in symptom scores [45]. In another study, two weeks of venlafaxine treatment increased the regional activity of the previously unresponsive right secondary visual cortex in MDD patients during the presentation of positive images under fMRI [46]. After receiving 14 sessions of cognitive behavioral therapy (CBT), MDD patients completed tasks including emotional response and emotional regulation under fMRI. Compared to the baseline before treatment, the down-regulation of BOLD activity in the precuneus, occipital lobe, and middle frontal gyrus predicts a better efficacy of CBT [47]. Interestingly, unconventional antidepressant treatments also have an impact on the visual cortex. In a double-blind placebo-controlled crossover trial, Furey’s group found that the activation of the middle occipital lobe (MOC) in control participants was significantly enhanced compared to patients with depression at baseline before scopolamine treatment [48]. MDD patients at baseline only show activation of the bilateral MOC when performing facial emotional working memory rather than facial recognition tasks, and the degree of MOC activation is positively correlated with the curative effects of scopolamine [48]. This study proposed that the MOC is central to the curative effect of rapid-onset antidepressants such as scopolamine, revealing that the MOC may be the neural basis of depression or antidepressant effects [48]. In addition, a long-term follow-up fMRI study of alleviated patients showed that the reactivity of the visual cortex is inversely correlated with recurrence in these patients, including distress tolerance. Compared with HCs, MDD patients in remission show a more obvious trade-off in the reactivity between the medial prefrontal cortex and visual cortex than HCs. The reactivity difference score between the two brain regions can better predict the recurrence of depression [49].
It is worth noting that although the above studies found dysfunction of the visual cortex in MDD through different visual emotional tasks, none of them involved treatment in the visual cortex. Our group designed a randomized, double-blind, and controlled clinical trial in which we used near-infrared neuronavigation, based on magnetic resonance, and demonstrated for the first time the antidepressant effect of targeting the visual cortex with transcranial magnetic stimulation (rTMS). Based on this trial, we proposed that the abnormal neural activity of the visual cortex is not only involved in emotional regulation but is also associated with a disorder of information processing and processing of depression [50]. In addition, we found that five consecutive days of rTMS in the visual cortex can improve the symptoms of MDD patients and increase the expression of circulating RNA of the dymeclin (DYM) gene (circDYM) in the plasma, and the expression of circDYM in MDD patients at baseline can effectively predict the efficacy of rTMS in the visual cortex [51].
Cerebral Blood Flow Changes
Studies have shown that the incidence of adolescent depression has increased sharply, the recurrence rate is high, and the functional prognosis is poor in child/adolescent MDD [52, 53]. As early as 1999, Bonte’s group had found occipital lobe perfusion defects in adolescent MDD patients during regional cerebral blood flow (rCBF) single-photon emission computed tomography (SPECT) [54]. Two years later, the same research group compared the rCBF of children with MDD and healthy children and found that some adolescent MDD patients had a marked defect in occipital lobe posterior blood flow, and the defect was usually symmetrical, while other patients preferentially showed a right frontal lobe rCBF defect [55]. The reason for this difference is unclear, and follow-up research is needed to further explore the relationship between CBF and MDD in children/adolescents. The occipital CBF in adults with MDD is also abnormal. A retrospective study based on SPECT of 98 inpatients showed that MDD patients had decreased bilateral occipital CBF unrelated to age [56]. However, an abnormal increase of rCBF in the occipital cortex (bilateral B17, B19, and left B18) has been reported in unipolar MDD [57]. These contradictory results might be explained by the fact that the clinical presentation may be one of the influencing factors for rCBF in the occipital lobe of MDD patients. Psychological pain is one of the easily neglected symptoms of depression. In MDD patients with a high degree of psychological pain, the cerebral perfusion of the right DLPFC, occipital lobe, inferior frontal gyrus, and left inferior temporal gyrus is relatively increased, while the medullary perfusion is reduced [58].
Changes in Visual Cortical Neurotransmitters and Metabolism
The level of γ-aminobutyric acid (GABA) in the occipital lobe was first reported in 1999 to be 52% lower in patients with MDD than HCs [59]. Subsequently, a correlation between neurotransmitters and depression was consistently found in different populations. Intravenous injection of the selective serotonin reuptake inhibitor (SSRI), citalopram (10 mg), produced an increase of 35% in the relative GABA concentration in the occipital lobe, as measured by proton magnetic resonance spectroscopy (1H-MRS), suggesting a direct action of SSRIs on cortical GABA neurons rather than a secondary consequence of mood improvement [60]. 1H-MRS showed that the level of glutathione in the occipital lobe of adolescent MDD patients is lower than that of healthy adolescents [61]. In addition to the decrease in GABA concentration [62], there is also an abnormal increase in the glutamate level in the occipital lobe of adult MDD patients [7, 63]. A study comparing the 1H-MRS data of patients with treatment-resistant depression (TRD) and non-TRD patients found that the level of GABA in the occipital lobe of TRD patients is 16.4% lower than that of non-TRD patients, suggesting that abnormality of the glutamate/glutamine/GABA cycle may be more serious in TRD patients [64]. Primary insomnia and MDD are closely associated in cross-sectional and longitudinal studies. 1H-MRS results showed that patients with primary insomnia have reduced GABA in the occipital lobe, similar to MDD patients [65]. It is worth noting that a recent study showed that patients with depression have abnormal visual motion, which is due to marked deficiencies in the concentrations of the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA in the brain area with sensory functions (the middle temporal lobe complex) [29]. Furthermore, studies have shown that the severity of anhedonia in MDD patients is negatively correlated with the level of glutathione in the occipital lobe, suggesting that there may be abnormal oxidative stress in the occipital lobe of MDD patients [66]. In addition, a study analyzing the postsynaptic brain GABA receptor of MDD patients with [123I] iomazenil SPECT demonstrated that although the decrease in GABA level in the occipital lobe of MDD patients is reproducible, there is no significant abnormality in the postsynaptic GABA receptors of the occipital lobe [67].
Different antidepressant therapies have potentially different mechanisms, and their effects on the level of GABA in the occipital lobe are also different. Eleven MDD patients who took oral SSRI antidepressant treatment for 2 months showed significantly improved levels of GABA in the occipital lobe [68], while electroconvulsive therapy in 8 MDD patients tripled the concentration of GABA in the occipital lobe [69]. However, there was no significant change in GABA levels in the occipital lobe of MDD patients receiving 12 weeks of CBT [70]. A significant decrease in GABA levels in the occipital lobe also exists in recovered MDD patients, significantly correlating with the recurrence rate of depression [71], while glutamate and glutamine levels are significantly higher in recovered MDD and BD patients [72]. However, the finding of a low occipital GABA in MDD has been challenged. In 2015, Godlewska et al. combined 1H-MRS with ultrashort echo time “special” technology to measure the levels of GABA, glutamate, and glutathione in the occipital lobe of MDD patients [73]. This study found no significant difference between the levels of GABA and glutamate in the occipital lobe of MDD patients and HCs, but the level of glutathione in MDD patients was significantly lower than that in HCs [73]. After 6 weeks of SSRI treatment, the depressive symptoms of MDD patients improved, but with no significant change in the GABA, glutamate, and glutathione levels [73].
As early as 1983, it was reported that the binding of imipramine in the occipital lobe of MDD patients was significantly reduced compared with HCs. The number of imipramine binding sites was reduced while receptor affinity remained normal [74]. In 2000, a small sample study found that treatment with the SSRI fluvoxamine can significantly improve the clinical symptoms of MDD patients and improve the uptake of [18F] fluoro-ethyl-spiperone ([18F]FESP) in the frontal and occipital lobes [75]. The increased binding of [18F]FESP may reflect a modification in serotonin (5-HT) receptor 2 binding capacity secondary to changes in cortical 5-HT activity [75]. A resting positron emission computed tomography (PET) readouts study showed that 8 weeks of treatment with the SSRI antidepressant citalopram improved emotional symptoms and cognitive function while increasing glucose metabolism in the occipital lobe of LLD patients [76]. Similarly, acute citalopram (40 mg) treatment also clearly elevated glucose metabolism in the occipital lobe of LLD patients, and chronic treatment with citalopram for 8 weeks increased glucose metabolism in the left occipital lobe [77]. In addition, PET-CT results showed that 5-HT2a receptor binding potential in the occipital lobe of MDD patients with remission for at least 6 months increased by an average of 19% compared with HCs [78]. The binding potential was positively correlated with the dysfunctional attitude score of MDD patients during remission [78].
Clinical Neurophysiology Studies of the Visual Cortex
The steady-state visual evoked potential has been used to detect attention bias and the capacity of working memory (WM) has been evaluated before and after the induction of negative emotion. In the study by Woody et al., rMDD women (a subgroup of MDD with a higher risk for recurrence) showed difficulty in suppressing attention to all emotional disruptors before negative emotion induction. The strongest effect was seen with negative distractors (sad faces). Among all women with rMDD, lower WM ability indicates that it is more difficult to suppress attention to negative and neutral distractors [79].
Many studies have shown that ketamine has a rapid and efficient antidepressant effect [80]. A recent meta-analysis has shown that intravenous ketamine has a better antidepressant effect than nasal spray [81]. A randomized, single-blind, crossover study using magnetoencephalography (MEG) evaluated task-related high-frequency oscillations of the visual and motor cortices in 20 HCs after intravenous injection of 0.5 mg/kg ketamine and found that ketamine increased the visual cortex β and γ band amplitude, but reduced the γ peak frequency [82]. Animal studies have shown that enhancement of the γ frequency band is associated with the disinhibition of cortical pyramidal cells [83]. Thus, regulation of the γ oscillation frequency by ketamine may underlie the basis of its rapid antidepressant effect and deserves further study. Ketamine can also quickly alleviate the depressive symptoms of patients with TRD. A double-blind, crossover, placebo-controlled study compared a single intravenous injection of ketamine hydrochloride (0.5 mg/kg) and a normal saline placebo in 19 untreated TRD patients and 15 HCs [84]. MEG data collected before and 6-9 h after injection showed that ketamine administration accelerated the transmission of GABA and N-methyl-D-aspartate in the early visual cortex (V1-V3), and led to direct and indirect changes in local inhibition of the early visual cortex and inferior frontal gyrus [84]. Moreover, reductions in depressive symptoms in TRD participants after treatment with ketamine are associated with faster α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid transmission and increased gain control of spiny stellate cells in the early visual cortex [84]. Although many 1H-MRS studies have shown that GABA concentration in the occipital lobe of MDD patients is significantly reduced, a MEG study of 19 female rMDD patients and 18 HCs showed no abnormality in the GABA system of both groups, but the early visual evoked response in the rMDD group was significantly impaired [85].
Clinical Histological and Molecular Biological Studies of the Visual Cortex
The reduced occipital lobe GABA level reported in 1H-MRS studies, although not found in MEG studies, is supported by histological examination. Using a three-dimensional cell counting probe on postmortem samples, a reduction in the density of calbindin-immunoreactive GABAergic neurons in layer II of the occipital lobe of MDD patients has been found [86]. Intriguingly, the size of these GABAergic neurons was unchanged in MDD patients compared to controls [86]. This study suggested that a deficit in cortical GABAergic interneurons may contribute to the lower GABA levels reported in neuroimaging studies of MDD patients.
A study using enzyme-linked immunosorbent assay in autopsy brain tissue samples showed that compared with drug-naive MDD patients and HCs, the level of brain-derived neurotrophic factor (BDNF) in the parietal cortex of treated MDD patients was significantly higher, while neurotrophic factor 3 levels in the parietal lobe, temporal occipital lobe, cingulate gyrus, thalamus, putamen, and caudate nucleus were also significantly increased [87]. This study revealed that antidepressant drugs mediate the changes in neural plasticity through the action of neurotrophic factor (NTF) [87]. These clinical studies suggest that GABAergic interneurons and NTF levels are altered in the visual cortex of depressed patients (Fig. 2). However, whether these abnormalities in the visual cortex are fundamentally involved in the etiology of MDD remains to be addressed.
Visual cortical neurotransmitter, metabolism, and molecular changes in depressed patients. The histological and molecular changes of the visual cortex in depressed patients or after antidepressant treatment. Red upward arrows indicate an increase in depression; red downward arrows indicate a decrease in depression; green upward arrows indicate an increase in recovered MDD or after therapy; green downward arrows indicate a decrease in recovered MDD or after therapy. 5-HT, serotonin; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CB, calbindin; [18F] FESP, [18F] fluoroethyl-spiperone; GABA, γ-aminobutyric acid; MDD, major depressive disorder; NMDA, N-methyl-D-aspartate; NTF, neurotrophic factor; V1, primary visual cortex; V3, visual association cortex.
Preclinical Studies
Animal models are valuable tools in which to explore mechanisms of visual cortical dysfunction in the context of depression (Fig. 3). Preclinical studies have shown that depression may lead to disorders of the sensory perception systems, including olfactory, auditory, visual, or gustatory [88]. Manganese-enhanced magnetic resonance imaging in mouse models of interferon-induced depression showed that the manganese uptake in the visual cortex was significantly lower than that in the control group, suggesting a dysfunction of the visual cortex [89]. In a rat depression model established by bilateral olfactory bulb resection, chronic administration of citalopram significantly diminished the regional cerebral glucose utilization [90]. Rs-fMRI showed that the regional homogeneity (ReHo) of the visual cortex in rats with chronic unpredictable mild stress (CUMS) was increased, while telmisartan, an adjuvant drug for MDD with memory impairment, reversed the abnormal changes of the visual cortex [91]. Based on ReHo analysis, the spontaneous activity of the visual cortex in CUMS mice is impaired and exercise significantly reduces CUMS-induced depression-like behaviors and increases the spontaneous activity in the visual cortex [92]. Male rats with both depression and erectile dysfunction are considered to have non-organic erectile dysfunction. fMRI in these animals indicated a central pathological mechanism of the visual cortex [93].
Visual cortical dysfunction in animal models of depression. The changes of neuronal activity, metabolism, synaptic plasticity, and neural circuits in the visual cortex in depressive animal models or after antidepressant treatment. Red upward arrows indicate an increase in animal models; red downward arrows indicate a decrease in animal models; green upward arrows indicate an increase after therapy; green downward arrows indicate a decrease after therapy. ABCA1, ATP-binding cassette transporter A1; ApoA1, apolipoprotein A1; c-MSST, combined magnetic stimulation system treatment; ECMS, early-life chronic mild stress; Ent, entorhinal cortex; V2M, secondary visual cortex.
An imbalance of neuronal excitatory (E) and inhibitory (I) signals in the 5-HT system of the neocortical network can lead to serious neurological diseases, including MDD. Patch clamp studies have found that 5-HT in the visual cortex can regulate the balance of E-I signals, suggesting its role in multisynaptic sensory circuits [94]. Liu and coworkers established a new mouse model of early-life chronic mild stress without anxiety or depression-like behavior in adulthood and found that these mice showed normal maturation of visual acuity and orientation/direction selectivity, while their visual cortical neurons displayed lower spatial frequency and higher temporal frequency than control mice [95]. Thus, early adverse experiences may have a lasting effect on the visual development of mice in a sex-dependent manner [95]. Intake of the SSRI antidepressant fluoxetine for four weeks can restore the ocular dominant plasticity and promote the recovery of visual function in adult amblyopic rats. These effects are accompanied by decreased inhibition in the cortex and increased BDNF expression in the visual cortex [96].
Fragile X pre-mutation phenotypes include anxiety, depression, social phobia, and memory defects. Mouse models of this condition have abnormal morphology in the pyramidal neurons of layer II/III of V1, resulting in abnormal synaptic circuits. This may be a fragile X-related characteristic lesion of the nervous system [97]. The orphan nuclear receptor gene Nurr1 is involved in the differentiation, maturation, and maintenance of dopaminergic neurons. When healthy adult mice are forced to swim, the expression of Nurr1 is upregulated rapidly and widely throughout the brain at 30 min or 3 h later, including the primary and secondary visual cortices, suggesting that the visual cortex is involved in the stress response through the Nurr1 gene [98].
In 2022, our research group independently developed a new precision magnetic stimulation technology, combined magnetic stimulation system treatment (c-MSST), and treated the left V1 regions in two mouse models of depression, CUMS and lipopolysaccharide-induced. The magnetoelectrical effect generated significant improvement in depression-like behavior over five days. We also analyzed the disease/efficacy-related protein, apolipoprotein A1 (ApoA1), and its interacting protein, ATP binding cassette transporter A1 (ABCA1), in the V1 region by high-throughput omics technology, and demonstrated that ABCA1/ApoA1 is associated with improved synaptic plasticity in the visual cortex at multiple levels, thus contributing to antidepressant efficacy [99].
Neural Circuit Research in Depressive Animal Models
In a mouse model of depression induced by long-term exposure to aversive stimuli or chronic social failure stress, light therapy can improve depression-like behavior with observable changes in synapses connecting the retina and the lateral habenula [100]. Although the study did not evaluate the role of the visual cortex in the antidepressant effect of light therapy, as the most important cerebral cortex for receiving and processing visual information, its role deserves further study.
It is worth noting that a new study in 2022 showed that neurons in layer 5A of the mouse entorhinal cortex (Ent) independently project to the medial area of the secondary visual cortex (V2M). Chronic social frustration stress is widely used to induce depression-like animal models with two phenotypes: stress-resistant and stress-sensitive. In stress-sensitive mice, the activity of neurons in layer 5A of the Ent is significantly decreased. Inhibition of the Ent-V2M pathway induces depression-like behavior in stress-resistant mice, while activation of this pathway in stress-sensitive mice significantly alleviates depression-like behavior. These results show that the Ent-V2M axis plays an important role in stress-induced depression-like behavior [101].
Conclusion
The etiology and mechanism of depression are complex. It is urgent to deeply explore the pathophysiological mechanism of depression. We believe that the importance of MDD visual cortical disorders is seriously underestimated. This review summarizes abnormalities in visual cortical structures and perfusion, information filtering, visual processing, spatial inhibition, motor visual perception, attention bias hypotheses such as visual emotion processing disorder, abnormalities in neurotransmitter levels, metabolism of the visual cortex, the connection of visual grid function, synaptic plasticity, and neural circuits. Clinical and preclinical findings suggest that the alterations of the visual cortex structure and function are closely associated with depression-related emotions, and antidepressants can change the electrophysiological characteristics and neurotransmitters of the visual cortex, thus extending our present insights of the possibility of visual cortical abnormalities in the pathogenesis and antidepressant mechanism of depression.
Although more and more evidence shows a relationship between MDD and visual cortex disorders, the research is still in its infancy, with many problems and limitations. First, most studies are small-sample clinical trials, and only a few clinical studies have used longitudinal designs, which may have a certain false positive rate and lead to partially contradictory results. Prospective and large-scale clinical trials should be designed to obtain more accurate results. Longitudinal studies are needed to evaluate how changes in clinical phenotype affect imaging or neurophysiological findings. Second, there is no unified standard for the design of visual tasks for participants, so consistent and comparable results are difficult to obtain. Optimizing visual tasks and finding the corresponding representation of different types of visual disorders and MDD are the key problems to be solved in the future. Third, at present, there are only a few studies directly targeting the visual cortex. In the future, techniques such as rTMS, theta burst stimulation, or c-MSST can be used to directly intervene in the visual cortex. Viral vectors or nanomaterials can be used to deliver drugs to the visual cortex, so as to find direct evidence of the involvement of the visual cortex in MDD and develop new intervention strategies. Finally, current studies on the visual cortex remain superficial. Most of the studies involve the whole occipital lobe and the visual cortex. In addition, it remains unclear whether positive findings are consequences and/or causes of depression. The possible interaction between different cell types in the visual cortex is a new research direction worthy of further exploration. Exploring the molecular mechanisms of depression to discover more effective, rapid, and precise targets for antidepressant drugs will become a new hot spot in the field of depression research. Identification of baseline biomarkers that predict and monitor the treatment response in MDD patients will provide important tools for personalized medicine.
References
World Health Organization. The Global Burden of Disease: 2004 Update. https://www.who.int/publications/i/item/9789241563710
Krishnan V, Nestler EJ. Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry 2010, 167: 1305–1320.
COVID-19 Mental Disorders Collaborators. Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. Lancet 2021, 398: 1700–1712.
Gold PW. The PPARg system in major depression: pathophysiologic and therapeutic implications. Int J Mol Sci 2021, 22: 9248.
Sokolowska E, Viitanen R, Misiewicz Z, Mennesson M, Saarnio S, Kulesskaya N. The circadian gene cryptochrome 2 influences stress-induced brain activity and depressive-like behavior in mice. Genes Brain Behav 2021, 20: e12708.
Li Z, Ruan M, Chen J, Fang Y. Major depressive disorder: Advances in neuroscience research and translational applications. Neurosci Bull 2021, 37: 863–880.
Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL, et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 2004, 61: 705–713.
Ancelin ML, Carrière I, Artero S, Maller J, Meslin C, Ritchie K, et al. Lifetime major depression and grey-matter volume. J Psychiatry Neurosci 2019, 44: 45–53.
Rubin-Falcone H, Zanderigo F, Thapa-Chhetry B, Lan M, Miller JM, Sublette ME, et al. Pattern recognition of magnetic resonance imaging-based gray matter volume measurements classifies bipolar disorder and major depressive disorder. J Affect Disord 2018, 227: 498–505.
Tomoda A, Polcari A, Anderson CM, Teicher MH. Reduced visual cortex gray matter volume and thickness in young adults who witnessed domestic violence during childhood. PLoS One 2012, 7: e52528.
Dixson L, Ridler K, Nichols TE, Saemann PG, Auer DP, Holsboer F, et al. Thyroid hormone transporter genes and grey matter changes in patients with major depressive disorder and healthy controls. Psychoneuroendocrinology 2011, 36: 929–934.
Zhou R, Wang F, Zhao G, Xia W, Peng D, Mao R, et al. Effects of tumor necrosis factor-α polymorphism on the brain structural changes of the patients with major depressive disorder. Transl Psychiatry 2018, 8: 217.
Miles AE, Dos Santos FC, Byrne EM, Renteria ME, McIntosh AM, Adams MJ, et al. Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk. Neuropsychopharmacology 2021, 46: 2304–2311.
Fullard K, Maller JJ, Welton T, Lyon M, Gordon E, Koslow SH, et al. Is occipital bending a structural biomarker of risk for depression and sensitivity to treatment? J Clin Neurosci 2019, 63: 55–61.
Ries A, Hollander M, Glim S, Meng C, Sorg C, Wohlschläger A. Frequency-dependent spatial distribution of functional hubs in the human brain and alterations in major depressive disorder. Front Hum Neurosci 2019, 13: 146.
de Haan EHF, Cowey A. On the usefulness of ‘what’ and ‘where’ pathways in vision. Trends Cogn Sci 2011, 15: 460–466.
Poeppl TB, Müller VI, Hoffstaedter F, Bzdok D, Laird AR, Fox PT, et al. Imbalance in subregional connectivity of the right temporoparietal junction in major depression. Hum Brain Mapp 2016, 37: 2931–2942.
Chen H, Liu K, Zhang B, Zhang J, Xue X, Lin Y, et al. More optimal but less regulated dorsal and ventral visual networks in patients with major depressive disorder. J Psychiatr Res 2019, 110: 172–178.
Lu F, Cui Q, Huang X, Li L, Duan X, Chen H, et al. Anomalous intrinsic connectivity within and between visual and auditory networks in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2020, 100: 109889.
Grayson L, Thomas A. A systematic review comparing clinical features in early age at onset and late age at onset late-life depression. J Affect Disord 2013, 150: 161–170.
Mai N, Wu Y, Zhong X, Chen B, Zhang M, Peng Q, et al. Different modular organization between early onset and late onset depression: a study base on granger causality analysis. Front Aging Neurosci 2021, 13: 625175.
Zhang F, Rao S, Cao H, Zhang X, Wang Q, Xu Y, et al. Genetic evidence suggests posttraumatic stress disorder as a subtype of major depressive disorder. J Clin Invest 2022, 132: e145942.
Bird CIV, Modlin NL, Rucker JJH. Psilocybin and MDMA for the treatment of trauma-related psychopathology. Int Rev Psychiatry 2021, 33: 229–249.
McGlade E, Rogowska J, DiMuzio J, Bueler E, Sheth C, Legarreta M, et al. Neurobiological evidence of sexual dimorphism in limbic circuitry of US Veterans. J Affect Disord 2020, 274: 1091–1101.
Desseilles M, Balteau E, Sterpenich V, Dang-Vu TT, Darsaud A, Vandewalle G, et al. Abnormal neural filtering of irrelevant visual information in depression. J Neurosci 2009, 29: 1395–1403.
Stephan-Otto C, Siddi S, Cuevas Esteban J, Senior C, García-Álvarez R, Cambra-Martí MR, et al. Neural activity during object perception in schizophrenia patients is associated with illness duration and affective symptoms. Schizophr Res 2016, 175: 27–34.
Shaffer JJ Jr, Johnson CP, Fiedorowicz JG, Christensen GE, Wemmie JA, Magnotta VA. Impaired sensory processing measured by functional MRI in Bipolar disorder manic and depressed mood states. Brain Imaging Behav 2018, 12: 837–847.
Golomb JD, McDavitt JRB, Ruf BM, Chen JI, Saricicek A, Maloney KH, et al. Enhanced visual motion perception in major depressive disorder. J Neurosci 2009, 29: 9072–9077.
Song XM, Hu XW, Li Z, Gao Y, Ju X, Liu DY, et al. Reduction of higher-order occipital GABA and impaired visual perception in acute major depressive disorder. Mol Psychiatry 2021, 26: 6747–6755.
Gögler N, Willacker L, Funk J, Strube W, Langgartner S, Napiórkowski N, et al. Single-session transcranial direct current stimulation induces enduring enhancement of visual processing speed in patients with major depression. Eur Arch Psychiatry Clin Neurosci 2017, 267: 671–686.
Frase L, Mertens L, Krahl A, Bhatia K, Feige B, Heinrich SP, et al. Transcranial direct current stimulation induces long-term potentiation-like plasticity in the human visual cortex. Transl Psychiatry 2021, 11: 17.
Eldar S, Apter A, Lotan D, Edgar KP, Naim R, Fox NA, et al. Attention bias modification treatment for pediatric anxiety disorders: a randomized controlled trial. Am J Psychiatry 2012, 169: 213–220.
Sylvester CM, Petersen SE, Luby JL, Barch DM. Face processing in adolescents with positive and negative threat bias. Psychol Med 2017, 47: 800–809.
Colich NL, Ho TC, Foland-Ross LC, Eggleston C, Ordaz SJ, Singh MK, et al. Hyperactivation in cognitive control and visual attention brain regions during emotional interference in adolescent depression. Biol Psychiatry Cogn Neurosci Neuroimaging 2017, 2: 388–395.
Chantiluke K, Halari R, Simic M, Pariante CM, Papadopoulos A, Giampietro V, et al. Fronto-striato-cerebellar dysregulation in adolescents with depression during motivated attention. Biol Psychiatry 2012, 71: 59–67.
Colich NL, Foland-Ross LC, Eggleston C, Singh MK, Gotlib IH. Neural aspects of inhibition following emotional primes in depressed adolescents. J Clin Child Adolesc Psychol 2016, 45: 21–30.
Keedwell PA, Andrew C, Williams SCR, Brammer MJ, Phillips ML. A double dissociation of ventromedial prefrontal cortical responses to sad and happy stimuli in depressed and healthy individuals. Biol Psychiatry 2005, 58: 495–503.
Keedwell PA, Drapier D, Surguladze S, Giampietro V, Brammer M, Phillips M. Subgenual cingulate and visual cortex responses to sad faces predict clinical outcome during antidepressant treatment for depression. J Affect Disord 2010, 120: 120–125.
Tak S, Lee S, Park CA, Cheong EN, Seok JW, Sohn JH, et al. Altered effective connectivity within the Fronto-limbic circuitry in response to negative emotional task in female patients with major depressive disorder. Brain Connect 2021, 11: 264–277.
van Dam WO, Chrysikou EG. Effects of unilateral tDCS over left prefrontal cortex on emotion regulation in depression: evidence from concurrent functional magnetic resonance imaging. Cogn Affect Behav Neurosci 2021, 21: 14–34.
Le TM, Borghi JA, Kujawa AJ, Klein DN, Leung HC. Alterations in visual cortical activation and connectivity with prefrontal cortex during working memory updating in major depressive disorder. Neuroimage Clin 2017, 14: 43–53.
Alders GL, Davis AD, MacQueen G, Strother SC, Hassel S, Zamyadi M, et al. Reduced accuracy accompanied by reduced neural activity during the performance of an emotional conflict task by unmedicated patients with major depression: a CAN-BIND fMRI study. J Affect Disord 2019, 257: 765–773.
Davidson RJ, Irwin W, Anderle MJ, Kalin NH. The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatry 2003, 160: 64–75.
Chechko N, Kellermann T, Augustin M, Zvyagintsev M, Schneider F, Habel U. Disorder-specific characteristics of borderline personality disorder with co-occurring depression and its comparison with major depression: an fMRI study with emotional interference task. Neuroimage Clin 2016, 12: 517–525.
Keedwell P, Drapier D, Surguladze S, Giampietro V, Brammer M, Phillips M. Neural markers of symptomatic improvement during antidepressant therapy in severe depression: subgenual cingulate and visual cortical responses to sad, but not happy, facial stimuli are correlated with changes in symptom score. J Psychopharmacol 2009, 23: 775–788.
Kalin NH, Davidson RJ, Irwin W, Warner G, Orendi JL, Sutton SK, et al. Functional magnetic resonance imaging studies of emotional processing in normal and depressed patients: effects of venlafaxine. J Clin Psychiatry 1997, 58: 32–39.
Rubin-Falcone H, Weber J, Kishon R, Ochsner K, Delaparte L, Doré B, et al. Neural predictors and effects of cognitive behavioral therapy for depression: the role of emotional reactivity and regulation. Psychol Med 2020, 50: 146–160.
Furey ML, Drevets WC, Hoffman EM, Frankel E, Speer AM, Zarate CA Jr. Potential of pretreatment neural activity in the visual cortex during emotional processing to predict treatment response to scopolamine in major depressive disorder. JAMA Psychiatry 2013, 70: 280–290.
Farb NAS, Anderson AK, Bloch RT, Segal ZV. Mood-linked responses in medial prefrontal cortex predict relapse in patients with recurrent unipolar depression. Biol Psychiatry 2011, 70: 366–372.
Zhang Z, Zhang H, Xie CM, Zhang M, Shi Y, Song R, et al. Task-related functional magnetic resonance imaging-based neuronavigation for the treatment of depression by individualized repetitive transcranial magnetic stimulation of the visual cortex. Sci China Life Sci 2021, 64: 96–106.
Song R, Bai Y, Li X, Zhu J, Zhang H, Shi Y, et al. Plasma circular RNA DYM related to major depressive disorder and rapid antidepressant effect treated by visual cortical repetitive transcranial magnetic stimulation. J Affect Disord 2020, 274: 486–493.
Dunn V, Goodyer IM. Longitudinal investigation into childhood- and adolescence-onset depression: psychiatric outcome in early adulthood. Br J Psychiatry 2006, 188: 216–222.
Thapar A, Collishaw S, Pine DS, Thapar AK. Depression in adolescence. Lancet 2012, 379: 1056–1067.
Bonte FJ. Brain blood flow SPECT: posterior flow deficits in young patients with depression. Clin Nucl Med 1999, 24: 696–697.
Bonte FJ, Trivedi MH, Devous MD Sr, Harris TS, Payne JK, Weinberg WA, et al. Occipital brain perfusion deficits in children with major depressive disorder. J Nucl Med 2001, 42: 1059–1061.
Nagafusa Y, Okamoto N, Sakamoto K, Yamashita F, Kawaguchi A, Higuchi T, et al. Assessment of cerebral blood flow findings using 99mTc-ECD single-photon emission computed tomography in patients diagnosed with major depressive disorder. J Affect Disord 2012, 140: 296–299.
Li J, Yang Y, Zhu Y, Zhou L, Han Y, Yin T, et al. Towards characterizing the regional cerebral perfusion in evaluating the severity of major depression disorder with SPECT/CT. BMC Psychiatry 2018, 18: 70.
van Heeringen K, Van den Abbeele D, Vervaet M, Soenen L, Audenaert K. The functional neuroanatomy of mental pain in depression. Psychiatry Res 2010, 181: 141–144.
Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OA, et al. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1999, 56: 1043–1047.
Bhagwagar Z, Wylezinska M, Taylor M, Jezzard P, Matthews PM, Cowen PJ. Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor. Am J Psychiatry 2004, 161: 368–370.
Freed RD, Hollenhorst CN, Weiduschat N, Mao X, Kang G, Shungu DC, et al. A pilot study of cortical glutathione in youth with depression. Psychiatry Res Neuroimaging 2017, 270: 54–60.
Song Z, Huang P, Qiu L, Wu Q, Gong Q, Zhang B, et al. Decreased occipital GABA concentrations in patients with first-episode major depressive disorder: a magnetic resonance spectroscopy study. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2012, 29: 233–236.
Meyer JH. Neurochemical imaging and depressive behaviours. Curr Top Behav Neurosci 2013, 14: 101–134.
Price RB, Shungu DC, Mao X, Nestadt P, Kelly C, Collins KA, et al. Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: relationship to treatment resistance in major depressive disorder. Biol Psychiatry 2009, 65: 792–800.
Plante DT, Jensen JE, Schoerning L, Winkelman JW. Reduced γ-aminobutyric acid in occipital and anterior cingulate cortices in primary insomnia: A link to major depressive disorder? Neuropsychopharmacology 2012, 37: 1548–1557.
Lapidus KAB, Gabbay V, Mao X, Johnson A, Murrough JW, Mathew SJ, et al. In vivo (1)H MRS study of potential associations between glutathione, oxidative stress and anhedonia in major depressive disorder. Neurosci Lett 2014, 569: 74–79.
Kugaya A, Sanacora G, Verhoeff NPLG, Fujita M, Mason GF, Seneca NM, et al. Cerebral benzodiazepine receptors in depressed patients measured with[123I]iomazenil SPECT. Biol Psychiatry 2003, 54: 792–799.
Sanacora G, Mason GF, Rothman DL, Krystal JH. Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 2002, 159: 663–665.
Sanacora G, Mason GF, Rothman DL, Hyder F, Ciarcia JJ, Ostroff RB, et al. Increased cortical GABA concentrations in depressed patients receiving ECT. Am J Psychiatry 2003, 160: 577–579.
Sanacora G, Fenton LR, Fasula MK, Rothman DL, Levin Y, Krystal JH, et al. Cortical gamma-aminobutyric acid concentrations in depressed patients receiving cognitive behavioral therapy. Biol Psychiatry 2006, 59: 284–286.
Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Boorman E, Matthews PM, et al. Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. Int J Neuropsychopharmacol 2008, 11: 255–260.
Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Ashworth F, Sule A, et al. Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psychiatry 2007, 61: 806–812.
Godlewska BR, Near J, Cowen PJ. Neurochemistry of major depression: a study using magnetic resonance spectroscopy. Psychopharmacology 2015, 232: 501–507.
Perry EK, Marshall EF, Blessed G, Tomlinson BE, Perry RH. Decreased imipramine binding in the brains of patients with depressive illness. Br J Psychiatry 1983, 142: 188–192.
Moresco RM, Colombo C, Fazio F, Bonfanti A, Lucignani G, Messa C, et al. Effects of fluvoxamine treatment on the in vivo binding of[F-18]FESP in drug naive depressed patients: a PET study. Neuroimage 2000, 12: 452–465.
Diaconescu AO, Kramer E, Hermann C, Ma Y, Dhawan V, Chaly T, et al. Distinct functional networks associated with improvement of affective symptoms and cognitive function during citalopram treatment in geriatric depression. Hum Brain Mapp 2011, 32: 1677–1691.
Smith GS, Kramer E, Hermann CR, Goldberg S, Ma Y, Dhawan V, et al. Acute and chronic effects of citalopram on cerebral glucose metabolism in geriatric depression. Am J Geriatr Psychiatry 2002, 10: 715–723.
Bhagwagar Z, Hinz R, Taylor M, Fancy S, Cowen P, Grasby P. Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100, 907. Am J Psychiatry 2006, 163: 1580–1587.
Woody ML, Miskovic V, Owens M, James KM, Feurer C, Sosoo EE, et al. Competition effects in visual cortex between emotional distractors and a primary task in remitted depression. Biol Psychiatry Cogn Neurosci Neuroimaging 2017, 2: 396–403.
de la Salle S, Phillips JL, Blier P, Knott V. Electrophysiological correlates and predictors of the antidepressant response to repeated ketamine infusions in treatment-resistant depression. Prog Neuro Psychopharmacol Biol Psychiatry 2022, 115: 110507.
Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord 2021, 278: 542–555.
Shaw AD, Saxena N, Jackson LE, Hall JE, Singh KD, Muthukumaraswamy SD. Ketamine amplifies induced gamma frequency oscillations in the human cerebral cortex. Eur Neuropsychopharmacol 2015, 25: 1136–1146.
Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 2007, 27: 11496–11500.
Gilbert JR, Galiano CS, Nugent AC, Zarate CA. Ketamine and attentional bias toward emotional faces: dynamic causal modeling of magnetoencephalographic connectivity in treatment-resistant depression. Front Psychiatry 2021, 12: 673159.
Shaw A, Brealy J, Richardson H, Muthukumaraswamy SD, Edden RA, John Evans C, et al. Marked reductions in visual evoked responses but not γ-aminobutyric acid concentrations or γ-band measures in remitted depression. Biol Psychiatry 2013, 73: 691–698.
Maciag D, Hughes J, O’Dwyer G, Pride Y, Stockmeier CA, Sanacora G, et al. Reduced density of calbindin immunoreactive GABAergic neurons in the occipital cortex in major depression: relevance to neuroimaging studies. Biol Psychiatry 2010, 67: 465–470.
Sheldrick A, Camara S, Ilieva M, Riederer P, Michel TM. Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) levels in post-mortem brain tissue from patients with depression compared to healthy individuals—a proof of concept study. Eur Psychiatry 2017, 46: 65–71.
Canbeyli R. Sensorimotor modulation of mood and depression: an integrative review. Behav Brain Res 2010, 207: 249–264.
Daducci A, Tambalo S, Fiorini S, Osculati F, Teti M, Fabene PF, et al. Manganese-enhanced magnetic resonance imaging investigation of the interferon-α model of depression in rats. Magn Reson Imaging 2014, 32: 529–534.
Skelin I, Sato H, Kovacević T, Diksic M. Chronic therapy with citalopram decreases regional cerebral glucose utilization in OBX, and not sham-operated, rats: an autoradiographic study. Psychopharmacology 2009, 207: 315–323.
Li J, Yang R, Xia K, Wang T, Nie B, Gao K, et al. Effects of stress on behavior and resting-state fMRI in rats and evaluation of Telmisartan therapy in a stress-induced depression model. BMC Psychiatry 2018, 18: 337.
Dong Z, Liu Z, Liu Y, Zhang R, Mo H, Gao L, et al. Physical exercise rectifies CUMS-induced aberrant regional homogeneity in mice accompanied by the adjustment of skeletal muscle PGC-1a/IDO1 signals and hippocampal function. Behav Brain Res 2020, 383: 112516.
Chen G, Yang B, Chen J, Zhu L, Jiang H, Yu W, et al. Changes in male rat sexual behavior and brain activity revealed by functional magnetic resonance imaging in response to chronic mild stress. J Sex Med 2018, 15: 136–147.
Moreau AW, Amar M, Le Roux N, Morel N, Fossier P. Serotoninergic fine-tuning of the excitation-inhibition balance in rat visual cortical networks. Cereb Cortex 2010, 20: 456–467.
Liu Y, Wang Z, Zhang X, Li S, Wu W, Li X, et al. A sex-dependent delayed maturation of visual plasticity induced by adverse experiences in early childhood. Neurobiol Stress 2020, 13: 100256.
Maya Vetencourt JF, Sale A, Viegi A, Baroncelli L, De Pasquale R, O’Leary OF, et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 2008, 320: 385–388.
Berman RF, Murray KD, Arque G, Hunsaker MR, Wenzel HJ. Abnormal dendrite and spine morphology in primary visual cortex in the CGG knock-in mouse model of the fragile X premutation. Epilepsia 2012, 53(Suppl 1): 150–160.
Rojas P, Joodmardi E, Perlmann T, Ogren SO. Rapid increase of Nurr1 mRNA expression in limbic and cortical brain structures related to coping with depression-like behavior in mice. J Neurosci Res 2010, 88: 2284–2293.
Lu Q, Wu F, Jiao J, Xue L, Song R, Shi Y, et al. Selective activation of ABCA1/ApoA1 signaling in the V1 by magnetoelectric stimulation ameliorates depression via regulation of synaptic plasticity. iScience 2022, 25: 104201.
Huang L, Xi Y, Peng Y, Yang Y, Huang X, Fu Y, et al. A visual circuit related to habenula underlies the antidepressive effects of light therapy. Neuron 2019, 102: 128-142.e8.
Lu J, Zhang Z, Yin X, Tang Y, Ji R, Chen H, et al. An entorhinal-visual cortical circuit regulates depression-like behaviors. Mol Psychiatry 2022, 27: 3807–3820.
Acknowledgements
This review was supported by grants from the National Natural Science Key Foundation of China (81830040 and 82130042), the China Science and Technology Innovation 2030-Major Project (2022ZD0211701 and 2021ZD0200700), the Science and Technology Program of Guangdong (2018B030334001), and the Science and Technology Program of Shenzhen (GJHZ20210705141400002, KCXFZ20211020164543006, JCYJ20220818101615033, and 202206063000055).
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Wu, F., Lu, Q., Kong, Y. et al. A Comprehensive Overview of the Role of Visual Cortex Malfunction in Depressive Disorders: Opportunities and Challenges. Neurosci. Bull. 39, 1426–1438 (2023). https://doi.org/10.1007/s12264-023-01052-7
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DOI: https://doi.org/10.1007/s12264-023-01052-7