Neuroimaging studies have revealed that dysfunction of reward circuitry in the brain underlies anhedonia, a core symptom of major depressive disorder (MDD) that is related to treatment outcomes. However, the relationship between the brain network at the level of neuronal oscillations and the longitudinal improvement in the severity of anhedonia is still unknown.

The study enrolled 84 unmedicated patients with MDD. Anhedonia severity was measured using the Snaith-Hamilton Pleasure Scale (SHAPS). EEG data in the resting state was obtained both at baseline and following an 8-week course of agomelatine 25 mg taken once daily. Whole-brain functional connectivity (FC) of source-level resting-state EEG and FC-derived graph metrics (i.e., global topological properties: global efficiency and local efficiency) were calculated in distinct frequency bands.

SHAPS scores were significantly improved from baseline to 8 weeks. Concurrently, there was a decrease in alpha-1 (8.5-10 Hz) connectivity between the right-hemisphere precuneus (PreC) and the left-hemisphere inferior frontal gyrus (IFG). Reduced alpha-2 (10.5-12 Hz) connectivity between the right-hemisphere transverse temporal gyrus (TTG) and the left-hemisphere superior frontal gyrus (SFG) and middle frontal gyrus (MFG) was observed. Global efficiency in the alpha-1 (p < 0.001) and alpha-2 (p = 0.003) frequency bands and local efficiency in the alpha-1 frequency band (p = 0.003) were reduced. Correlation analyses showed that alpha-1 local efficiency at baseline predicted improvement in SHAPS scores (r = -0.261, p = 0.017).

Global topological properties of source-level EEG FC can predict anhedonia improvement during antidepressant treatment, which might help guide treatment decisions and advance precision psychopharmacology.

Recent breakthroughs in electroactive piezo-biomaterials have driven significant progress towards the development of both, diagnostic and therapeutic purposes, enabling vital sign monitoring, such as heart rate, etc. while also supporting tissue regeneration. Bioelectronic medicine provides a promising method for controlling tissue and organ functions, with 'piezo-electronics' emphasizing the lasting role of electro-active piezo-biomaterials in self-powered devices. This article critically analyses a range of self-powered bioelectronic technologies, including wearable, implantable, regenerative, and cancer therapy applications. Piezoelectric nanogenerators (PENGs) are essential in wearable and implantable systems such as pressure and strain measurements, sensor for human-machine interface, self-powered pacemakers, deep brain stimulation, cochlear implant, tissue restoration and sustained drug delivery, controlled by electrical stimuli from PENGs etc. Regenerative bioelectronics play a key role in healing tissues, such as bone, neural, cardiac, tendon, ligament, skeletal muscle etc. using self-powered implants, which have ability to restore tissue functionality. Additionally, piezoelectric biomaterials are being utilized in cancer treatment, offering more targeted therapies with minimal side effects. Various cancerous tumors can be destroyed by reactive oxygen species (ROS), generated by piezo-biomaterials. Data science is also emerging as a crucial tool in optimizing self-powered bioelectronics, enhancing patient outcomes through data-driven strategies, and broadening the role of bioelectronic technologies in modern healthcare.

The globus pallidus plays a pivotal role in the basal ganglia circuit. Parkinson's disease is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson's disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson's disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore, bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico-striato-pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson's disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson's disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson's disease, particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremor-dominant and non-tremor-dominant Parkinson's disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia-thalamus network. Therefore, the composition of the globus pallidus neurons, the neurotransmitters that act on them, their electrical activity, and the neural circuits they form can guide the search for new multi-target drugs to treat Parkinson's disease in clinical practice. Examining the potential intra-nuclear and neural circuit mechanisms of deep brain stimulation associated with the globus pallidus can facilitate the management of both motor and non-motor symptoms while minimizing the side effects caused by deep brain stimulation.

Psychiatric disorders are a common source of disease morbidity with high rates of refractoriness to first-line treatments. As such, many have investigated the utility of neurosurgical interventions for treatment-resistant forms of these conditions. More recently among these, functional neurosurgical techniques using high- and low-intensity focused ultrasound (FUS) have emerged as promising options in this arena, largely due to their minimally-invasive nature and encouraging early safety and efficacy data. Existing clinical data have thus far demonstrated FUS to be a potentially useful intervention for treatment-refractory forms of obsessive-compulsive disorder, major depressive disorder, various anxiety disorders, substance-use disorder, and schizophrenia. This report presents a comprehensive review of existing clinical trial data, summarizing key findings, study specifications, and providing critical analysis. In addition to giving the most complete summary of modern clinical research on this topic to date, this report characterizes the current state of this body of literature using bibliometric analysis, succinctly highlighting the most investigated topics and the most promising areas of modern investigation. Based on our review of the literature, current work on this topic is highly heterogeneous with regard to specific treatment protocols and anatomic targets for FUS - targeting multiple nuclei at a wide variety of intensities. We recommend that future studies aim to clarify more precise therapeutic targets and specific treatment protocols which optimize the efficacy of these techniques.

The delta opioid receptor (DOP) is a promising target for novel antidepressants due to its potential for rapid action with minimal adverse effects; however, the functional mechanism underlying acute antidepressant actions remains elusive. We report that subcutaneous injection of the selective DOP agonist KNT-127 reduced immobility in the forced swimming test, and that this antidepressant-like response was reversed by intracerebroventricular injection of the selective mechanistic (or mammalian) target of rapamycin (mTOR) inhibitor rapamycin or the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002. KNT-127 also alleviated social avoidance and reduced sucrose consumption (anhedonia) among chronic vicarious social defeat stress model mice, which were similarly reversed by PI3K and mTOR inhibitors. In addition, KNT-127 increased phosphorylation levels of the mTOR signaling-related proteins Akt and p70S6 kinase in medial prefrontal cortex as revealed by immunoblotting. In the forced swimming test, a microinfusion of KNT-127 and another DOP agonist SNC80 in the infralimbic prefrontal cortex (IL-PFC) attenuated the immobility, which were blocked by rapamycin and LY294002. Perfusion of KNT-127 onto IL-PFC slices increased miniature excitatory postsynaptic current frequency and reduced miniature inhibitory postsynaptic current frequency in pyramidal neurons as measured by whole-cell patch-clamping, and both responses were reversed by rapamycin. Imaging of brain slices from transgenic mice with DOP-promoter-driven green fluorescent protein revealed that most DOPs were expressed in parvalbumin-positive interneurons in the IL-PFC. These findings suggest that DOP agonists exert antidepressant-like actions by suppressing GABA release from parvalbumin-positive interneurons via the PI3K-Akt-mTORC1-p70S6 kinase pathway, thereby enhancing IL-PFC pyramidal neuron excitation.

Non-invasive Brain Stimulation (NIBS) technologies, including transcranial electrical (tES) and magnetic (TMS) stimulation, have emerged as promising interventions for various psychiatric disorders. FDA-approved TMS protocols in depression, OCD and nicotine use disorder provide a meaningful improvement. Treatment efficacy however remains inconsistent across individuals, and one relevant reason is intervention effect variability based on individual factors. There is a growing effort to develop individualized interventions, reinforced recently by FDA approval of a new TMS protocol that includes individualized fMRI-based targeting along with other modifications with higher reported effect size than previous "one size fits all" protocols. This paper discusses the dimensions for individualizing tES/TMS protocols to enhance therapeutic efficacy. We propose a multifaceted approach to personalizing NIBS, considering four levels: (1) context, (2) target, (3) dose, and (4) timing. By addressing inter- and intra-individual variability, we highlight a path toward precision medicine using individualized Brain Stimulation to treat psychiatric diseases. Despite challenges and limitations, this approach encourages broader and more systematic adoption of personalized Brain Stimulation techniques to improve clinical outcomes.

The purpose of this review is to evaluate the current state and potential future directions of deep brain stimulation (DBS) therapy for treatment-resistant depression (TRD), a condition that significantly impacts patients' quality of life and for which conventional treatments are often ineffective.

This review synthesizes evidence from clinical trials and preclinical studies published in five years, identified through PubMed searches using keywords ("Deep Brain Stimulation" OR DBS) AND ("Treatment-Resistant Depression" OR TRD). Included studies encompassed clinical research (randomized/non-randomized trials, cohort studies) and mechanistic preclinical studies, excluding non-English publications and nonhuman experiments. Screening prioritized neuroanatomical targets (e.g., SCG, NAcc) and stimulation parameter optimization data. Examining the therapeutic mechanisms of DBS, the neuroanatomical targets utilized, and the clinical outcomes observed. It also discusses the challenges faced in DBS application and proposes potential technological advancements, such as closed-loop therapy and fiber tracking technology.

Preliminary evidence exists regarding the efficacy and safety of DBS in the treatment of TRD in the subcortical cingulate gyrus (SCG), nucleus accumbens (NAcc), ventral capsule/ventral striatum (VC/VS), anterior limb of the internal capsule (ALIC), and so forth. Nevertheless, the optimal stimulation target remains undetermined. The review highlights the complexity of TRD and the need for personalized treatment strategies, noting that genetic, epigenetic, and neurophysiological changes are implicated in DBS's therapeutic effects.

In conclusion, while DBS for TRD remains an experimental therapy, it offers a unique and potentially effective treatment option for patients unresponsive to traditional treatments. The review emphasizes the need for further research to refine DBS targets and parameters, improve patient selection, and develop personalized treatment plans to enhance efficacy and safety in TRD management.

Neuromodulation of deep brain regions has shown promise for treatment-resistant depression (TRD). However, it currently requires neurosurgical electrode implantation, posing significant risks and limiting widespread use while TRD affects around 100 million people worldwide. Low-intensity transcranial ultrasound stimulation (TUS) could allow precise and non-invasive deep neuromodulation, provided that the challenge of the defocusing effects of the skull is tackled.

Here, we present the development of a portable and neuronavigated TUS prototype based on the use of patient-specific metamaterials (metalens) that correct for skull-induced aberrations. We then present the first application of metalens-based Transcranial Ultrasound Stimulation (mTUS) in TRD. The primary objective was to assess the safety and efficacy of mTUS targeting on individual level specific white matter tracts of the subcallosal cingulate involved in TRD.

The safety and precision of this device was addressed through a series of numerical simulations and experimental measurements on ex vivo human skulls. Five participants with TRD were included in this open-label study (ClinicalTrials.gov identifier: NCT06085950) and underwent an intensive 5-day course of mTUS with a total of 25 sessions of 5 min each.

No serious adverse events occurred during the study. By day 5 of treatment, depression severity was reduced by an average of 60.9 % (range: [30 %-83.9 %]), and four out of five patients qualified as responders, with two of them in remission.

This study provides first-in-human evidence of the potential of mTUS as a precise, safe and effective non-invasive neuromodulation technique for neuropsychiatric disorders involving deep brain regions, offering a safer and more accessible alternative to invasive approaches.

The prefrontal cortex (PFC) is a brain region involved in higher-order cognitive processes such as attention, emotional regulation, and social behavior. However, the delineation of distinct subdivisions within the mouse PFC and their contributions to the broader brain network function remain debated. This study utilizes resting-state functional magnetic resonance imaging (MRI) from a cohort of 100 C57BL/6J wild-type mice to derive the functional connectivity (FC)-based parcellation of the mouse PFC with voxel resolution. Our findings reveal clusters that deviate from the established anatomical subdivisions within the cingulate and prelimbic areas while aligning in infralimbic and orbital cortices. Upon the chemogenetic perturbation of one of the clusters, FC perturbations occur only within the functional network linked to the targeted cluster and do not spread to neighboring anatomical areas or functional clusters. We propose FC-based parcellation as a valuable approach for tracking the site of activation and network impact of neurostimulation strategies.

Depression is a chronic disorder that impacts millions worldwide. Traditional treatments may not always work. Inflammation seems to be an underlying cause for chronicity and treatment non-response.

We present a computational model that elucidates the interplay between inflammation, serotonin levels, and brain activity.

The model delineates how inflammation impacts extracellular serotonin, while cerebral activity reciprocally influences serotonin concentration. Understanding the reciprocal interplay between the immune system and brain dynamics is important, as unabated inflammation can lead to relapsing depression. The model predicts dynamics within the prefrontal cortex (PFC) and subcallosal cingulate cortex (SCC), mirroring patterns observed in depressive conditions. It also accommodates pharmaceutical interventions that encompass anti-inflammatory and antidepressant agents, concurrently evaluating their efficacy with regard to the severity of depressive symptoms Our model shows that for mild and moderate levels of depression anti-depressant agents or anti-inflammatory agents acting in isolation can bring serotonergic levels and brain activity to control levels. However, for severe depression only joint treatment of anti-depressant and anti-inflammatory agents can bring the serotonergic levels and activity to control levels.

This study is a first step to mechanistically understand the intricate link between the immune system and depression, the role of inflammation and potential treatments. It explores the impact of anti-depressant and anti-inflammatory drug treatments and assesses their relevance with regard to depression severity.

Modern psychiatry faces challenges in translating neurobiological insights into treatments for severe illnesses. The mid-20th century witnessed the rise of molecular mechanisms as pathophysiological and treatment models, with recent holistic proposals keeping this focus unaltered. In this perspective, we explore how psychiatry can utilize systems neuroscience to develop a vertically integrated understanding of brain function to inform treatment. Using schizophrenia as a case study, we discuss scale-related challenges faced by researchers studying molecules, circuits, networks, and cognition and clinicians operating within existing frameworks. We emphasize computation as a bridging language, with algorithmic models like hierarchical predictive processing offering explanatory potential for targeted interventions. Developing such models will not only facilitate new interventions but also optimize combining existing treatments by predicting their multi-level effects. We conclude with the prognosis that the future is bright, but that continued investment in research closely driven by clinical realities will be critical.

Cortical stimulation with single pulses is a common technique in clinical practice and research. However, we still do not understand the extent to which it engages subcortical circuits that may contribute to the associated evoked potentials (EPs). Here we show that cortical stimulation generates remarkably similar EPs in humans and mice, with a late component similarly modulated by the state of the targeted cortico-thalamic network. We then optogenetically dissect the underlying circuit in mice, demonstrating that the EPs late component is caused by a thalamic hyperpolarization and rebound. The magnitude of this late component correlates with bursting frequency and synchronicity of thalamic neurons, modulated by the subject's behavioral state. A simulation of the thalamo-cortical circuit highlights that both intrinsic thalamic currents as well as cortical and thalamic GABAergic neurons contribute to this response profile. We conclude that single pulse cortical stimulation engages cortico-thalamo-cortical circuits largely preserved across different species and stimulation modalities.

Severe forms of depression have been linked to excessive subcallosal cingulate cortex (SCC) activity. Stimulation of the SCC with surgically implanted electrodes can alleviate depression, but current noninvasive techniques cannot directly and selectively modulate deep targets. We developed a new noninvasive neuromodulation approach that can deliver low-intensity focused ultrasonic waves to the SCC.

Twenty-two individuals with treatment-resistant depression participated in a randomized, double-blind, sham-controlled study. Ultrasonic stimulation was delivered to the bilateral SCC during concurrent functional magnetic resonance imaging to quantify target engagement. Mood state was measured with the Sadness subscale of the Positive and Negative Affect Schedule before and after 40 minutes of real or sham SCC stimulation. Change in depression severity was measured with the 6-item Hamilton Depression Rating Scale at 24 hours and 7 days.

Functional magnetic resonance imaging demonstrated a target-specific decrease in SCC activity during stimulation (p = .028, n = 16). In 7 of 16 participants, SCC neuromodulation was detectable at the individual participant level with a single 10-minute scan (p < .05, small-volume correction). Mood and depression scores improved more with real than with sham stimulation. In the per-protocol sample (n = 19), real stimulation was superior to sham for 6-item Hamilton Depression Rating Scale scores at 24 hours and for Sadness scores (both p < .05, d > 1). Nonsignificant trends were found in the intent-to-treat sample.

This small pilot study indicates that ultrasonic stimulation modulates SCC activity and can rapidly reduce depressive symptoms. The capability to noninvasively and selectively target deep brain areas creates new possibilities for the future development of circuit-directed therapeutics and for the analysis of deep-brain circuit function in humans.

Deep Brain Stimulation (DBS) is a critical intervention for various neurological disorders. While effective, the traditional local infiltration anesthesia used in DBS surgeries often hinders electrophysiological recording quality and patient cooperativeness. The research aims to evaluate the impact of local infiltration versus scalp block anesthetic methods on electrophysiological signal quality and patient cooperativeness during DBS surgeries. This study involved patients who participated in an intraoperative task during the bilateral subthalamic nucleus DBS surgery for Parkinson's Disease between Jan 2020 and Dec 2022. Patients were either administered the traditional local infiltration anesthesia or the modified scalp block anesthesia. Intraoperative electrophysiological recording data and anesthetic data was collected. Spike sorting was performed to evaluate the recording stability. Patient cooperativeness and intraoperative experience was assessed and compared. The patients under scalp block anesthesia exhibited shorter pre-acquisition time, longer stable recording time, higher number of tasks per site, higher number of neurons recorded per task (all ps < 0.05). In behavior, patients under scalp block anesthesia showed higher accuracy in tasks (p < 0.05), while the response time was comparable. The overall satisfaction of anesthesia was also higher in scalp block, as revealed by the visual analogue scale, Likert scale and mean arterial pressure (all ps < 0.05). The modified scalp block anesthetic method offers considerable advantages over traditional local infiltration anesthesia in DBS surgeries. It helps to improve both patient comfort and cooperation during the surgery, and thereby enhancing the overall quality of neurological data and efficacy of DBS procedures.

Major depression is characterized by an array of negative experiences, including hopelessness and anhedonia. We hypothesize that inhibition of negative experiences or aversion may generate antidepressant action. To directly test this hypothesis, we perform multimodal behavioral screenings in male mice and identify somatostatin (SST)-expressing neurons in the region X (HBX) between the lateral and medial habenula as a specific type of antidepressant neuron. SST neuronal activity modulation dynamically regulates antidepressant induction and relief. We also explore the circuit basis for encoding these modulations using single-unit recordings. We find that SST neurons receive inhibitory synaptic inputs directly from cholecystokinin-expressing neurons in the bed nucleus of the stria terminalis and project excitatory axon terminals onto proenkephalin-expressing neurons in the interpeduncular nucleus. This study reveals a cell-type-specific circuit of SST neurons in the HBX that encodes antidepressant action, and the control of the circuit may contribute to improving well-being.

Expression of the N-methyl-D-aspartate receptor, particularly when containing the GluN2B subunit (NMDAR-GluN2B), varies across the prefrontal cortex (PFC). In humans, the subgenual cingulate cortex (SGC) contains among the highest levels of NMDAR-GluN2B expression, while the dorsolateral prefrontal cortex (dlPFC) exhibits a more moderate level of NMDAR-GluN2B expression. NMDAR-GluN2B are commonly associated with ionotropic synaptic function and plasticity and are essential to the neurotransmission underlying working memory in the macaque dlPFC in the layer III circuits, which in humans are afflicted in schizophrenia. However, NMDAR-GluN2B can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked to neurodegenerative processes. The SGC is an early site of tau pathology in sporadic Alzheimer's disease (sAD), which mirrors its high NMDAR-GluN2B expression. Additionally, the SGC is hyperactive in depression, which can be treated with NMDAR antagonists. Given the clinical relevance of NMDAR in the SGC and dlPFC, the current study used immunoelectron microscopy (immunoEM) to quantitatively compare the synaptic and extrasynaptic expression patterns of NMDAR-GluN2B across excitatory and inhibitory neuron dendrites in rhesus macaque layer III SGC and dlPFC. We found a larger population of extrasynaptic NMDAR-GluN2B in dendrites of putative pyramidal neurons in SGC as compared to the dlPFC, while the dlPFC had a higher proportion of synaptic NMDAR-GluN2B. In contrast, in putative inhibitory dendrites from both areas, extrasynaptic expression of NMDAR-GluN2B was far more frequently observed over synaptic expression. These findings may provide insight into varying cortical vulnerability to alterations in excitability and neurodegenerative forces.

Transcranial Direct Current Stimulation (tDCS) has shown potential in modulating cortical activity and treating depression. Despite its promise, variability in electrode montage configurations and electric field strength across studies has resulted in inconsistent outcomes. Traditional meta-analytic methods assessing the effect of tDCS in depression typically do not compare tDCS montage and the anatomical distribution of electric field, which is a major source of inter-experimental variability. We hypothesize that considering these parameters and anatomical variability in a meta-analysis might unravel brain regions associated with tDCS response in patients with depression. We correlate the clinical outcome (Effect size) with electric field intensities across 8 diverse head models, analyzing data from 29 studies involving 1766 patients between 2000 and 2023. Our analysis found a significant effect of tDCS on depression, with a Hedge's g = 0.66 (95 % CI: 0.565 to 0.767). Although studies aimed to target the L-DLPFC, particularly Brodmann area (BA) 46, based on the Frontal Brain Asymmetry theory, our findings show that all the montages do not selectively target the L-DLPFC as intended. Instead, our findings indicated that the electric field impact was dispersing broadly across the frontal lobes and exhibiting significant heterogeneity. We found a correlation between electric field strength and clinical outcomes in BA 10, BA 11, and the anterior part of BA 46 despite tDCS montages heterogeneity and individual variability, suggesting that targeting frontopolar prefrontal and orbitofrontal cortices could be ideal for tDCS in treating depression. Our work underscores brain regions associated with tDCS response and highlights the need for simulation-guided, personalized trials that consider individual anatomical differences.

The field of neuromodulation has evolved tremendously and now includes a vast array of interventions utilizing different technologies that span electrical, magnetic, and ultrasound forms of stimulation. The evolution of interventions holds the promise of fewer adverse effects and a noninvasive approach, increasing the scale at which these interventions may be offered in hospital and community settings. While the majority of neuromodulation studies have focused on patients with mood disorders, predominantly depression, there is an unmet need for patients with schizophrenia, who are in dire need of novel therapeutic options. Advances in neuroimaging and approaches for examining individual variability and transdiagnostic symptoms may lead to more effective neuromodulation treatments in this patient population. This overview explores the modern landscape of invasive and noninvasive neuromodulation treatments for patients with schizophrenia. It begins with approaches that involve diffuse stimulation of the cortex and subcortex and then reviews more focal stimulation approaches at the cortical and subcortical levels. The authors also reflect on the relationship between our understanding of the neurobiology of schizophrenia and neuromodulation interventions.

Individualized transcranial magnetic stimulation (TMS) targeting using functional connectivity analysis of functional magnetic resonance imaging (fMRI) has been demonstrated to be advantageous in inducing neuroplasticity. However, how this approach can benefit modulating the episodic memory function supported by the hippocampal network remains elusive. We use the resting-state fMRI data from a large cohort to reveal tentative TMS targets at cortical regions within the hippocampal network. Functional MRI from 1,133 individuals in the Human Connectome Project was used to analyze the hippocampal network using seed-based functional connectivity. Using a weighted sum of time series at the cortex, we identified the average centroids of individualized targets at the medial prefrontal cortex (mPFC) and posterior parietal cortices (PPCs) at (-10, 49, 7) and (-40, -67, 30) in the left hemisphere, respectively. The mPFC and PPC coordinate at the right hemispheres are (11, 51, 6) and (48, -59, 24) in the right hemisphere, respectively. Centroids of the individualized functional connectivity at the mPFC and PPC were reproducible between sessions with separations in average about 2 and 4 mm, respectively. These separations were significantly smaller than the distance to average functional connectivity centroids (~10 mm) and atlas coordinate (~20 mm). These coordinates can be reliably identified (> 90% of individuals) using cortical "seedmaps." Our results suggest candidate TMS target coordinates to modulate the hippocampal function.

Major depressive disorder (MDD) is associated with hypoactivity in the frontoparietal (FP) system and hyperactivity in the limbic (LM) system. The widely accepted limbic-cortical dysregulation model has recently been extended by the concept of imbalanced reciprocal suppression between these 2 systems. This study investigates the refined theoretical framework. Neuroimaging datasets from 60 MDD and 60 healthy controls were obtained from the Canadian Biomarker Integration Network in Depression database, including structural magnetic resonance imaging (MRI) and resting-state functional MRI (rsfMRI). The cerebral cortex was parcellated using the modular analysis and similarity measurements (MOSI) technique. For each node, the average amplitude of low-frequency fluctuation (avgALFF) and nodal strength were calculated. Correlation analyses were conducted to establish an adjacency matrix and assess the relationship between nodal power and strength. The results indicated that the LM system in MDD displayed higher partition numbers and avgALFF (P < 0.005). A significant negative correlation between nodal strength and power was replicated (P < 1E-10), suggesting that greater functional input enhances regional neural suppression. Notably, MDD participants exhibited a higher negative correlation between FP nodal power and LM-FP connectivity (stronger suppression) but a lower negative correlation between LM nodal power and FP-LM connectivity (weaker suppression). These findings support the theory of abnormal cortical signal organization and reciprocal suppression in MDD.

Depression is a heterogeneous disorder with diverse clinical presentations and etiological underpinnings, necessitating the identification of distinct subtypes to enhance targeted interventions. Dissociative symptoms, commonly observed in major depressive disorder (MDD) and linked to early life trauma, may represent a unique clinical dimension associated with specific neurocognitive deficits. Although emerging research has begun to explore the role of dissociation in depression, most studies have provided only descriptive analyses, leaving the mechanistic interplay between these phenomena underexplored. The primary objective of this study is to determine whether MDD patients with prominent dissociative symptoms differ from those without such symptoms in clinical presentation, neurocognitive performance, and markers of functional connectivity. This investigation will be the first to integrate comprehensive clinical evaluations, advanced neurocognitive testing, and high-resolution brain imaging to delineate the contribution of dissociative symptoms in MDD.

We will recruit fifty participants for each of three groups: (1) depressive patients with dissociative symptoms, (2) depressive patients without dissociative symptoms, and (3) healthy controls. Diagnostic assessments will be performed using the Structured Clinical Interview for DSM-5 (SCID) alongside standardized scales for depression severity, dissociation, and childhood trauma. Neurocognitive performance will be evaluated through a battery of tests assessing memory, attention, executive function, and processing speed. Structural and functional magnetic resonance imaging (MRI) will be conducted on a 3 Tesla scanner, focusing on the connectivity of the Default Mode Network with key regions such as the orbitofrontal cortex, insula, and posterior cingulate cortex. Data analyses will employ SPM-12 and Matlab-based CONN and PRONTO tools, with multiclass Gaussian process classification applied to differentiate the three groups based on clinical, cognitive, and imaging data.

The results of this study will introduce a novel perspective on understanding the connection between major depressive disorder and dissociation. It could also aid in pinpointing a distinct form of depression associated with dissociative symptoms and early childhood stressors.

Future research, aiming to forecast the response to biological and psychological interventions for depression, anticipates this subtype and provides insights.

Treatment-resistant depression (TRD) remains a vital challenge in psychiatry, affecting a significant number of patients with major depressive disorder. Current pharmacological approaches often do not provide sufficient therapeutic results, prompting the need for innovative treatments. This review summarizes recent advances in TRD management, including non-pharmacological therapies such as transcranial magnetic stimulation, deep brain stimulation, electroconvulsive therapy, and vagus nerve stimulation, and describes their mechanisms of action. Novel pharmacotherapies, particularly glutamatergic modulators like ketamine and esketamine, have shown promising results with esketamine being available to eligible patients in Poland since 2023 within a drug program. Electroconvulsive therapy remains an effective treatment for TRD, usually with small side effects mainly including transient memory impairment, headache, or cardiovascular changes. Transcranial magnetic stimulation is a non-invasive procedure with proven efficacy; therefore several psychiatric organizations recommend it as a treatment option for major depressive disorder in their clinical guidelines. Deep brain stimulation is a relatively new treatment modality for TRD, with its primary risk being associated with the required neurosurgical procedure. Vagus nerve stimulation seems to be a promising adjunctive treatment for TRD, showing significant improvements in depressive symptoms, especially at higher electrical doses but with no side effects. While these treatments appear to have potential, personalized approaches are crucial for optimizing outcomes. Future research should focus on refining the techniques, improving safety profiles, and validating the long-term efficacy.

Deep brain stimulation (DBS) is a promising treatment for refractory depression, utilizing surgically implanted electrodes to stimulate specific anatomical targets within the brain. However, limitations of patient-reported and clinician-administered mood assessments pose obstacles in evaluating DBS treatment efficacy. In this study, we investigated whether an affective bias task, which leverages the inherent negative interpretation bias seen in individuals with depression, could serve as a reliable measure of mood changes during DBS therapy in patients with treatment-resistant depression.

Two cohorts of patients (n = 8, n = 2) undergoing DBS for treatment-resistant depression at different academic medical centers completed an affective bias task at multiple time points before and after DBS implantation. The affective bias task involved rating the emotional content of a series of static photographic stimuli of facial expressions throughout their DBS treatment. Patients' ratings were compared with those of non-depressed controls to calculate affective bias scores. Linear mixed-effects modeling was used to assess changes in bias scores over time and their relationship with depression severity measured by the Hamilton Depression Rating Scale (HDRS-17).

We observed significant improvements in total affective bias scores over the course of DBS treatment in both cohorts. Pre-DBS, patients exhibited a negative affective bias, which was nearly eliminated post-DBS, with total bias scores approaching those of non-depressed controls. Positive valence trials showed significant improvement post-DBS, while negative valence trials showed no notable change. A control analysis indicated that stimulation status did not significantly affect bias scores, and thus stimulation status was excluded from further modeling. Linear mixed-effects modeling revealed that more negative bias scores were associated with higher HDRS-17 scores, particularly for positive valence stimuli. Additionally, greater time elapsed since DBS implantation was associated with a decrease in HDRS-17 scores, indicating clinical improvement over time.

Our findings demonstrate that the affective bias task leverages the inherent negative interpretation bias seen in individuals with depression, providing a standardized measure of how these biases change over time. Unlike traditional mood assessments, which rely on subjective introspection, the affective bias task consistently measures changes in mood, offering potential as a tool to monitor mood changes and evaluate the candidacy of DBS treatment in refractory depression.

Objective.This work introduces Dareplane, a modular and broad technology-agnostic open source software platform for brain-computer interface (BCI) research with an application focus on adaptive deep brain stimulation (aDBS). One difficulty for investigating control approaches for aDBS resides with the complex setups required for aDBS experiments, a challenge Dareplane tries to address.Approach.The key features of the platform are presented and the composition of modules into a full experimental setup is discussed in the context of a Python-based orchestration module. The performance of a typical experimental setup on Dareplane for aDBS is evaluated in three benchtop experiments, covering (a) an easy-to-replicate setup using an Arduino microcontroller, (b) a setup with hardware of an implantable pulse generator, and (c) a setup using an established and CE certified external neurostimulator. The full technical feasibility of the platform in the aDBS context is demonstrated in a first closed-loop session with externalized leads on a patient with Parkinson's disease receiving DBS treatment and further in a non-invasive BCI speller application using code-modulated visual evoked potential (c-VEP).Main results.The platform is implemented and open-source accessible onhttps://github.com/bsdlab/Dareplane. Benchtop results show that performance of the platform is sufficient for current aDBS latencies, and the platform could successfully be used in the aDBS experiment. The timing-critical c-VEP speller could be successfully implemented on the platform achieving expected information transfer rates.Significance.The Dareplane platform supports aDBS setups, and more generally the research on neurotechnological systems such as BCIs. It provides a modular, technology-agnostic, and easy-to-implement software platform to make experimental setups more resilient and replicable.

One of the fundamental challenges for modern neuroscience has been to translate discoveries from model organisms into effective therapeutics for human brain disorders. This challenge partly arises from the structural and functional differences between rodent and human brains [1]. To bridge this gap, non-human primates (NHPs) can be used as an intermediate step because of their genetic, physiological, and behavioral similarities to humans. Among NHPs, the common marmoset has become a valuable animal model in neuroscience research due to its fast generation time and unique biological and behavioral characteristics [2]. In this review, we first summarize the progress toward developing models for brain disorders. We then discuss emerging technologies and resources that will help advance our understanding of the neurobiological mechanisms underlying different brain disorders using marmoset genetic models. Finally, we describe using marmoset models to test novel therapeutic approaches such as gene therapy and neural circuit manipulation.

Imbalance in inhibitory and excitatory neurotransmitters have been reported in tinnitus. Acamprosate modulates the excitatory and inhibitory neurotransmission in the nucleus accumbens (NAc). This study aims to assess the effect of Acamprosate on tinnitus, anxiety, depression, and molecular changes in nucleus accumbens (NAc), in Sodium-Salisylate (S-salicylate) model of tinnitus.

Forty-four adult male wistar rats were used in this study. The study included Control, Saline, and S-salicylate groups during the first week, which then subdivided into five groups as Control, Saline, S-salicylate, Acamprosate, and S-salicylate+Acamprosate. Gap-in Noise (GIN) and pre-pulse inhibition (PPI) were used to assessment of tinnitus at baseline, day7 and day14. Anxiety and depression were evaluated on day 14, by elevated plus maze (EPM), open field (OF), and tail suspension (TST) tests. The protein expression of GABAAR-δ, NR1 and NR2B in NAc were also measured using western blot technique.

After seven days GIN reduced in S-salicylate compare to Control and Saline groups (P < 0.5), while PPI unchanged. After 14 days, GIN reduced in S-salicylate and S-salicylate+Acamprosate groups compare to Control; Saline; and Acamprosate groups (P < 0.5). Additionally, GIN was higher in S-salicylate+Acamprosate compare to S-salicylate group (P < 0.5). PPI was not changed after 14 days. Open arm time in EPM test was decreased in S-salicylate and S-salicylate+Acamprosate groups compare to Control; Saline; and Acamprosate groups (P < 0.5). Central Zone time in OF test was reduced in S-salicylate group compare to Control, Saline, Acamprosate, and S-salicylate+Acamprosate groups (P < 0.5). Immobility Time in TST was increased in S-salicylate group compare to Control, Saline, Acamprosate, and S-salicylate+Acamprosate groups (P < 0.5). GABAAR-δ was decreased in S-salicylate groups compare to Control, Saline, Acamprosate; and S-salicylate+Acamprosate groups (P < 0.5). NR1 and NR2B in NAc were increased in S-salicylate group compare to Control, Saline, Acamprosate, and S-salicylate+Acamprosate groups (P < 0.5).

S-salicylate can induce tinnitus-like behaviors in rat. Furthermore, S-salicylate induced depression/anxiety like behaviors, and changed the expression of GABAR and NMDAR subunits in NAc. Acamprosate partially reversed these changes. In conclusion, NAc may be involved in the pathophysiologic mechanisms of tinnitus.

Brain aging contributes to cognitive decline and risk of dementia. Degeneration of the basal forebrain cholinergic system parallels these changes in aging, Alzheimer's dementia, Parkinson's dementia, and Lewy body dementia, and thus is a common element linked to executive function across the lifespan and in disease states. Here, we tested the potential of one-hour daily intermittent basal forebrain stimulation to improve cognition in senescent Rhesus monkeys, and its mechanisms of action. Stimulation in five animals improved working memory duration in each animal over 8-12 weeks, with peak improvements observed in the first four weeks. In an ensuing three month period without stimulation, improvements were retained. With additional stimulation, performance remained above baseline throughout the 15 months of the study. Studies with a cholinesterase inhibitor in five animals produced inconsistent improvements in behavior. One of five animals improved significantly. Manipulating the stimulation pattern demonstrated selectivity for both stimulation and recovery period duration in two animals. Brain stimulation led to acute increases in cerebrospinal fluid levels of tissue plasminogen activator, which is an activating element for two brain neurotrophins, Nerve Growth Factor (NGF) and Brain-Derived Growth Factor (BDNF), in four animals. Stimulation also led to improved glucose utilization in stimulated hemispheres relative to contralateral in three animals. Glucose utilization also consistently declines with aging and some dementias. Together, these findings suggest that intermittent stimulation of the nucleus basalis of Meynert improves executive function and reverses some aspects of brain aging.

Major depressive disorder (MDD) is usually considered associate with immune inflammation and synaptic injury within specific brain regions. However, the molecular mechanisms underlying the neural deterioration resulting in depression remain unclear. Here, it is found that miR-204-5p is markedly downregulated in the ventromedial prefrontal cortex (vmPFC) in a chronic unpredictable mild stress (CUMS) induce rat model of depression. Knockdown of miR-204-5p in the vmPFC of normal rats results in depression and anxiety-like behaviors accompanied with the activation of microglia, elevated levels of pro-inflammatory cytokines, and increased numbers of neural apoptotic cells, effects which appear to be mediated by activation of the JAK2/STAT3 signaling pathway. Electrophysiological recordings further demonstrate that knockdown of miR-204-5p induces abnormal excitability of pyramidal neurons. In contrast, upregulation of miR-204-5p in the vmPFC of CUMS rats significantly causes inhibition of JAK2/STAT3 signaling pathway, improvements in neuronal impairments, and an abolition of the depression and anxiety-like behaviors. Moreover, pharmacological blocking of the JAK2/STAT3 signaling pathway significantly ameliorates abnormal behaviors resulting from miR-204-5p deficiency within the vmPFC. Collectively, these results provide robust evidence that the miR-204-5p/JAK2/STAT3 pathway may critically involve in the pathogenesis of depression, which may serve as potentially critical therapeutic target in the treatment of MDD.

Stereotactic procedures are used to manage a diverse set of patients across a variety of clinical contexts. The stereotactic devices and software used in these procedures vary between surgeons, but the fundamental principles that constitute safe and accurate execution do not. The aim of this work is to describe these principles to equip readers with a generalizable knowledge base to execute and understand stereotactic procedures.

A combination of a review of the literature and empirical experience from several experienced surgeons led to the creation of this work. Thus, this work is descriptive and qualitative by nature, and the literature is used to support instead of generate the ideas of this framework.

The principles detailed in this work are categorized based on 5 clinical domains: imaging, registration, mechanical accuracy, target planning and adjustment, and trajectory planning and adjustment. Illustrations and tables are used throughout to convey the concepts in an efficient manner.

Stereotactic procedures are complex, requiring a thorough understanding of each step of the workflow. The concepts described in this work enable functional neurosurgeons with the fundamental knowledge necessary to provide optimal patient care.

Tinnitus arises from the intricate interplay of multiple, parallel but overlapping networks, involving neuroplastic changes in both auditory and non-auditory activity. Tailor-made notched music training (TMNMT) has emerged as a promising therapeutic approach for tinnitus. Residual inhibition (RI) represents one of the rare interventions capable of temporarily alleviating tinnitus, offering a valuable tool that can be applied to tinnitus research to explore underlying tinnitus mechanisms. To our knowledge, this study is the first to investigate the neural mechanisms underlying the RI effect of TMNMT through analysis of neural source activity and functional connectivity of EEG. Forty-four participants with tinnitus were divided into TMNMT group (twenty-two participants; ECnm, NMnm, RInm represented that EEG recordings with eyes closed stimuli-pre, stimuli-ing, stimuli-post by TMNMT music, respectively) and Placebo control group (twenty-two participants; ECpb, PBpb, RIpb represented that EEG recordings with eyes closed stimuli-pre, stimuli-ing, stimuli-post by Placebo music, respectively) in a single-blind manner. Source localization analysis revealed that RI effect of TMNMT significantly increased in current density at the delta band in the insula, subgenual anterior cingulate cortex (sgACC), parahippocampus (PHC), and secondary auditory cortex (AⅡ), and significantly increased in current density at the theta band in the sgACC, and significantly decreased in current density at the alpha band in the precuneus, PHC, primary (AI) and secondary (AII) auditory cortex. Meanwhile, RI effect of Placebo significantly decreased in current density at the alpha band in the PHC. Functional connectivity analysis demonstrated that RI effect of TMNMT significantly increased in phase coherence between the left AⅡ and the right sgACC; and between the left PHC and the left retrosplenial cortex (RSC) at the theta band. It significantly decreased in phase coherence between the left PHC and the right precuneus, the right posterior cingulate cortex (PCC), the right AⅡ; between the right PHC and the right PCC; and between the right PCC and the right AⅡ at the alpha band. RI effect of Placebo significantly increased in phase coherence between the left insula and the right precuneus, the left PHC, the right PHC, the left AⅠ, the left AⅡ; between the left sgACC and the right PHC; between the left AⅡ and the right PHC, the left PCC at the delta band. It was found that the current density of sgACC was significantly positively correlated with the tinnitus evaluation indicators (Loudness, VAS, THI, TFI) at the alpha band in TMNMT group. These findings indicated that TMNMT, a novel music therapy for tinnitus, revealed a robust RI effect, and RI effect of TMNMT was not only involved in the activity of auditory networks (AⅠ, AⅡ), but also extended to non-auditory networks, particularly higher-level auditory association cortices, such as the sgACC, PHC and PCC. The current study provides valuable experimental evidence and promising practical prospects for the potential applications of TMNMT in tinnitus treatment.

The subcallosal cingulate gyrus (SCG) is integral to cognitive function and mood regulation. Open-label SCG deep brain stimulation (DBS) studies demonstrate improvement or stabilisation of cognitive function in treatment-resistant depression (TRD).

This randomised controlled study aims to evaluate the neuropsychological effects of SCG-DBS.

35 participants with TRD received active or sham stimulation over two 3-month periods. A neuropsychological battery was administered to assess processing speed, learning and memory, and cognitive flexibility. Composite measures were derived for each domain after Period I. A mixed model for repeated measures analysis was performed for each test, with further analysis of significant measures to determine sustainability after Period II.

No significant differences in changes in depression scores were observed between groups. There were no significant deteriorations in cognitive performance following active SCG-DBS. Category Fluency Test performance improved after 3 months of active SCG-DBS (p=0.002); however, this was non-significant after correcting for multiple comparisons and was not observed after Period II (p=0.615).

While no cognitive deterioration was observed following SCG-DBS, significant improvements in cognitive function were not evident. There may be a transient enhancement in processing speed; however, this effect is not fully understood. Future studies should include larger cohorts and extended stimulation periods to explore the long-term effects of SCG-DBS in TRD and the sustainability of improvements in cognitive domains.

Depression is a complex mental illness that has significant effects on people as well as society. The traditional techniques for the diagnosis of depression, along with the potential of nascent biomarkers especially EEG-based biomarkers, are studied. This review explores the significance of cognitive biomarkers, offering a comprehensive understanding of their role in the overall assessment of depression. It also investigates the effects of depression on various brain regions, outlines promising areas for future research, and emphasizes the importance of understanding the neurophysiological roots of depression. Furthermore, it elucidates how machine learning and deep learning models are integrated into EEG-based depression diagnosis, emphasizing their importance in optimizing personalized therapeutic protocols and improving diagnostic accuracy with EEG data analysis.

This article presented the author's historical perspective on 25 of the most significant neurosurgical breakthrough events of the last 50 years. These breakthroughs have advanced neurosurgical patient care and management. They have improved the management of aneurysms, arteriovenous malformations, tumors, stroke, traumatic brain injury, movement disorders, epilepsy, hydrocephalus, and spine pathologies. Neurosurgery has evolved through research, innovation, and technology. Several neurosurgical breakthroughs were achieved using neuroendoscopy, neuronavigation, radiosurgery, endovascular techniques, and refinements in computer technology. With these breakthroughs, neurosurgery did not change; it just progressed. Neurosurgery should continue its progress through research to obtain new knowledge for the benefit of our patients.

Objective.Transcranial electrical stimulation (TES) is an effective technique to modulate brain activity and treat diseases. However, TES is primarily used to stimulate superficial brain regions and is unable to reach deeper targets. The spread of injected currents in the head is affected by volume conduction and the additional spreading of currents as they move through head layers with different conductivities, as is discussed in Forssellet al(2021J. Neural Eng.18046042). In this paper, we introduce DeepFocus, a technique aimed at stimulating deep brain structures in the brain's 'reward circuit' (e.g. the orbitofrontal cortex, Brodmann area 25, amygdala, etc).Approach.To accomplish this, DeepFocus utilizes transnasal electrode placement (under the cribriform plate and within the sphenoid sinus) in addition to electrodes placed on the scalp, and optimizes current injection patterns across these electrodes. To quantify the benefit of DeepFocus, we develop the DeepROAST simulation and optimization platform. DeepROAST simulates the effect of complex skull-base bones' geometries on the electric fields generated by DeepFocus configurations using realistic head models. It also uses optimization methods to search for focal and efficient current injection patterns, which we use in our simulation and cadaver studies.Main results.In simulations, optimized DeepFocus patterns created larger and more focal fields in several regions of interest than scalp-only electrodes. In cadaver studies, DeepFocus patterns created large fields at the medial orbitofrontal cortex (OFC) with magnitudes comparable to stimulation studies, and, in conjunction with established cortical stimulation thresholds, suggest that the field intensity is sufficient to create neural response, e.g. at the OFC.Significance.This minimally invasive stimulation technique can enable more efficient and less risky targeting of deep brain structures to treat multiple neural conditions.

Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction, and the thoughtful regulation of attention, action, and emotion. For example, schizophrenia, depression, long COVID, and Alzheimer's disease are all associated with dlPFC dysfunction, with neuropathology often being focused in layer III. The dlPFC has extensive top-down projections, e.g., to the posterior association cortices to regulate attention and to the subgenual cingulate cortex via the rostral and medial PFC to regulate emotional responses. However, the dlPFC is particularly dependent on arousal state and is very vulnerable to stress and inflammation, which are etiological and/or exacerbating factors for most mental disorders. The cellular mechanisms by which stress and inflammation impact the dlPFC are a topic of current research and are summarized in this review. For example, the layer III dlPFC circuits that generate working memory-related neuronal firing have unusual neurotransmission, depending on NMDA receptor and nicotinic α7 receptor actions that are blocked under inflammatory conditions by kynurenic acid. These circuits also have unusual neuromodulation, with the molecular machinery to magnify calcium signaling in spines needed to support persistent firing, which must be tightly regulated to prevent toxic calcium actions. Stress rapidly weakens layer III connectivity by driving feedforward calcium-cAMP (cyclic adenosine monophosphate) opening of potassium channels on spines. This is regulated by postsynaptic noradrenergic α2A adrenergic receptor and mGluR3 (metabotropic glutamate receptor 3) signaling but dysregulated by inflammation and/or chronic stress exposure, which contribute to spine loss. Treatments that strengthen the dlPFC via pharmacological (the α2A adrenergic receptor agonist, guanfacine) or repetitive transcranial magnetic stimulation manipulation provide a rational basis for therapy.

Expression of the N-methyl-D-aspartate receptor, particularly when containing the GluN2B subunit (NMDAR-GluN2B) varies across the prefrontal cortex (PFC). In humans, the subgenual cingulate cortex (SGC) contains among the highest levels of NMDAR-GluN2B expression, while the dorsolateral prefrontal cortex (dlPFC) exhibits a more moderate level of NMDAR-GluN2B expression. NMDAR-GluN2B are commonly associated with ionotropic synaptic function and plasticity, and are essential to the neurotransmission underlying working memory in the macaque dlPFC in the layer III circuits afflicted in schizophrenia. However, NMDAR-GluN2B can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked to neurodegenerative processes. The SGC is an early site of tau pathology in sporadic Alzheimer's Disease (sAD), which mirrors its high NMDAR-GluN2B expression. Additionally, the SGC is hyperactive in depression, which is treated with NMDAR antagonists. Given the clinical relevance of NMDAR in the SGC and dlPFC, the current study used immunoelectron microscopy (immunoEM) to quantitatively compare the synaptic and extrasynaptic expression patterns of NMDAR-GluN2B across excitatory and inhibitory neuron dendrites in the rhesus macaque SGC and dlPFC. We found a larger population of extrasynaptic NMDAR-GluN2B in dendritic shafts and spines of putative pyramidal neurons in SGC as compared to the dlPFC, while the dlPFC had a higher proportion of synaptic NMDAR-GluN2B. In contrast, in putative inhibitory dendrites from both areas, extrasynaptic expression of NMDAR-GluN2B was far more frequently observed over synaptic expression. These findings may provide insight into varying cortical vulnerability to alterations in excitability and to neurodegenerative forces.

NMDAR are ionotropic receptors that contribute to neurotransmission and second messenger signaling events. NMDAR can induce a diverse array of neuronal events, in part due to variation in subunit composition and subcellular localization of receptor expression. Expression of the GluN2B subunit varies across the prefrontal cortex in humans. This subunit is highly expressed in the subgenual cingulate, an area associated with mood and emotion, and more moderately expressed in the dorsolateral prefrontal cortex, an area associated with cognitive processes. Extrasynaptic NMDAR, which often contain with the GluN2B subunit, have been linked to detrimental cellular events like neurodegeneration. Here, using high resolution electron microscopy in rhesus macaques, we found evidence that extrasynaptic NMDAR-GluN2B expression may be more prominent in subgenual cortex than in the dorsolateral prefrontal cortex. Conversely, synaptic NMDAR-GluN2B may be more prominent in the dorsolateral prefrontal cortex, consistent with their essential contribution to neuronal firing during working memory. These findings may help to illuminate the propensity of the subgenual cortex to tonic hyperactivity in major depression and its vulnerability to neurodegeneration in Alzheimer's disease, and may help to explain how rapid acting antidepressants exert therapeutic action across diverse neural circuits.

The emotion regulation network (ERN) in the brain provides a framework for understanding the neuropathology of affective disorders. Although previous neuroimaging studies have investigated the neurobiological correlates of the ERN in major depressive disorder (MDD), whether patients with MDD exhibit abnormal functional connectivity (FC) patterns in the ERN and whether the abnormal FC in the ERN can serve as a therapeutic response signature remain unclear.

A large functional magnetic resonance imaging dataset comprising 709 patients with MDD and 725 healthy controls (HCs) recruited across five sites was analyzed. Using a seed-based FC approach, we first investigated the group differences in whole-brain resting-state FC of the 14 ERN seeds between participants with and without MDD. Furthermore, an independent sample (45 MDD patients) was used to evaluate the relationship between the aforementioned abnormal FC in the ERN and symptom improvement after 8 weeks of antidepressant monotherapy.

Compared to the HCs, patients with MDD exhibited aberrant FC between 7 ERN seeds and several cortical and subcortical areas, including the bilateral middle temporal gyrus, bilateral occipital gyrus, right thalamus, calcarine cortex, middle frontal gyrus, and the bilateral superior temporal gyrus. In an independent sample, these aberrant FCs in the ERN were negatively correlated with the reduction rate of the HAMD17 score among MDD patients.

These results might extend our understanding of the neurobiological underpinnings underlying unadaptable or inflexible emotional processing in MDD patients and help to elucidate the mechanisms of therapeutic response.