The study, published in Annals of General Psychiatry, examined 431 people diagnosed with depression and 422 healthy controls. Participants were between 18 and 45 years old, right-handed, and recruited through the psychiatry department of an affiliated university hospital in China. Three senior psychiatrists confirmed depression diagnoses using structured clinical interviews based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. The researchers also used the Hospital Anxiety and Depression Scale to quantify depressive symptoms. The depression group scored substantially higher than the healthy group, while the two groups did not differ significantly in age. Participants with other psychiatric disorders, major medical illnesses, substance-use problems, brain injuries or severe cognitive limitations were excluded.

To observe the brain while it was working, the researchers used functional near-infrared spectroscopy, or fNIRS. Unlike magnetic resonance imaging, fNIRS does not require a large scanner. Instead, a cap-like array places light emitters and detectors on the scalp. Near-infrared light at wavelengths of 760 and 850 nanometres penetrates the skull and is partly absorbed by blood oxygen-carrying molecules. When a brain region becomes more engaged, local blood flow generally increases, changing the relative concentrations of oxygenated and deoxygenated haemoglobin. The instrument recorded these changes across 53 channels covering the frontal poles, bilateral dorsolateral prefrontal regions and frontopolar cortex. Because oxygenated haemoglobin typically provides a stronger task-related signal, the researchers focused their main analysis on changes in oxyhaemoglobin.

The participants completed a verbal fluency task, a deceptively simple test that places heavy demands on executive control. After a 30-second counting period, each person heard a Chinese character and had 60 seconds to produce as many accurate two-character words as possible. They then completed a 60-second recovery period while counting aloud. Generating words under time pressure requires the brain to retrieve information from memory, suppress inappropriate responses, shift between possible answers and maintain attention on the rules of the task. These processes depend heavily on frontoparietal networks, particularly the dorsolateral prefrontal cortex. The task therefore offered the researchers a controlled way to examine how depression and sex interacted during cognitive effort rather than simply measuring brain activity at rest.

The researchers processed the optical recordings to remove physiological noise and movement-related distortions. Raw light intensities were converted into optical-density changes, and transient motion spikes were corrected with a wavelet-based method. A 0.01-to-0.10-hertz bandpass filter reduced interference from breathing, heartbeat and slow signal drift. Low-quality channels were removed when their coefficient of variation exceeded 15 percent during the task. The cleaned signals were then converted into haemoglobin concentration changes using the modified Beer–Lambert law, a mathematical model that estimates how light absorption relates to chromophore concentration in tissue. Task-related activation was calculated by comparing oxyhaemoglobin levels during the verbal fluency block with the preceding baseline.

The strongest sex-dependent pattern emerged in two channels corresponding to the left dorsolateral prefrontal cortex. Among participants with depression, women showed significantly lower oxyhaemoglobin activation than men in both channels. Within the female comparison, women with depression also showed lower activation in one of these channels than healthy women. The statistical interaction between sex and diagnostic group was marginally significant in the two left dorsolateral prefrontal channels, with probability values of 0.098 and 0.089, while the direct comparisons between depressed men and women were significant. These results point toward a particularly pronounced alteration in the left dorsolateral prefrontal cortex among women with depression, although the marginal interaction values mean the finding requires replication and should not be treated as a definitive biological boundary.

A different signal appeared in men. In the channel corresponding to the right frontal eye field, the interaction between sex and diagnostic group was statistically significant, with a probability value of 0.019. Men with depression showed lower activation in this region than healthy men, although the within-male comparison itself was described as marginally significant. The frontal eye field is best known for initiating voluntary and reflexive eye movements, including rapid saccades, but its role is broader than motor control. It forms part of the machinery that allocates spatial attention, selects relevant visual information and links perception to action. Reduced recruitment of this region could therefore reflect difficulties in shifting attention, searching efficiently or suppressing competing responses during cognitive activity. The result does not show that depression in men is caused by a malfunctioning eye-movement centre; rather, it identifies a region whose task-related blood-oxygen response differed between groups.

The left dorsolateral prefrontal cortex has a different functional profile. It maintains and manipulates information in working memory, helps form intentions, organizes goal-directed behaviour and contributes to the regulation of emotional information. It also communicates with sensory, premotor, parietal and limbic regions, making it a hub where thought, action and feeling can interact. Lower activation during verbal fluency could be consistent with the cognitive symptoms frequently reported in depression, such as slowed thinking, impaired concentration, difficulty making decisions and problems sustaining goal-directed behaviour. The researchers propose that the left dorsolateral prefrontal cortex may be a key location where the neural architecture of depression diverges between men and women. That interpretation is compatible with earlier neuroimaging studies linking depression to prefrontal dysfunction, but it remains an association rather than proof that the altered activity causes symptoms.

The results could eventually influence how researchers design treatments and biomarkers for depression, but they do not justify using a brain scan to diagnose an individual patient today. fNIRS is relatively inexpensive, portable and tolerant of natural movement, making it attractive for psychiatric research and potentially for repeated measurements during treatment. Yet the technique measures haemodynamic changes near the cortical surface, not electrical activity directly, and signals can be contaminated by blood flow in the scalp. The study did not use short-separation channels, which are designed to measure and regress out this superficial noise. It was also cross-sectional, so the researchers cannot determine whether the observed patterns precede depression, result from recurrent illness or change when symptoms improve. Most participants were young adults, and the task’s word-production performance was not analysed alongside the brain data. Future longitudinal studies spanning adolescence to older age, with detailed anxiety assessments, behavioural performance measures and improved physiological controls, will be needed to test whether sex-specific brain patterns can predict symptoms, treatment response or recovery.

Subject of Research: Sex-specific prefrontal brain activation patterns in depression during a verbal fluency task

Article Title: Divergent prefrontal activation between genders in depression during verbal fluency task: evidence from a large-scale fNIRS study

Article References: Zhang, Y., Zhang, Z., Zheng, M. et al. “Divergent prefrontal activation between genders in depression during verbal fluency task: evidence from a large-scale fNIRS study.” Annals of General Psychiatry 25, 34 (2026). Original research article

Image Credits: AI Generated

DOI: 10.1186/s12991-026-00648-3

Keywords: depression, sex differences, prefrontal cortex, dorsolateral prefrontal cortex, frontal eye field, verbal fluency task, functional near-infrared spectroscopy, fNIRS, executive function

Historically overshadowed by more extensively studied brain regions such as the prefrontal cortex and hippocampus, the habenula’s role in mood regulation has only recently garnered significant attention. Despite its modest size, the habenula serves as a critical hub integrating motivational and emotional information by modulating midbrain monoaminergic systems. This unique position allows it to influence reward processing, aversive stimuli response, and ultimately behavioral adaptation, processes often disrupted in MDD.

One of the most intriguing insights gleaned from both animal studies and imaging data in humans is the habenula’s role in encoding negative reward prediction errors—signals that occur when outcomes are worse than expected. Hyperactivity of the lateral habenula has been consistently observed in depressed subjects and correlated with symptoms such as anhedonia and helplessness. This hypermetabolic state appears to inhibit dopaminergic neuron firing in the ventral tegmental area, depressing reward-related signaling pathways that are essential for motivation and pleasure.

Preclinical models have been particularly instrumental in dissecting the underlying cellular and molecular mechanisms driving habenula abnormalities in depression. Rodent experiments demonstrate that chronic stress—a known precipitant of depression—induces synaptic potentiation within the lateral habenula, leading to exaggerated output to downstream monoaminergic centers. Interestingly, optogenetic modulation of this circuitry can reverse depressive-like behaviors in these models, underscoring the habenula’s functional significance and potential as a therapeutic target.

In human neuroimaging studies, advanced techniques such as high-resolution fMRI have enabled precise delineation of habenula structure and activity in depressed patients. These investigations confirm the lateral habenula’s hyperactivity correlates with symptom severity and treatment resistance. Moreover, emerging evidence suggests that habenular volume reductions may accompany chronic mood disorders, hinting at structural plasticity associated with long-term disease progression.

The habenula’s extensive reciprocal connections with serotonergic, dopaminergic, and noradrenergic nuclei place it at the crossroads of the brain’s major neurotransmitter systems implicated in mood regulation. Disruptions in this network could result in imbalances manifesting as the core symptoms of depression—low mood, impaired motivation, and cognitive dysfunction. These insights support a revised conceptual framework wherein the habenula is not merely an accessory structure but a driver of depressive pathology.

Crucially, the habenula is gaining traction as a novel focal point for neuromodulatory interventions. Deep brain stimulation (DBS) targeting the lateral habenula has shown promise in small cohorts of treatment-resistant depression patients, producing notable symptomatic improvements. These findings align with preclinical evidence that precise modulation of habenula firing patterns can restore normal monoaminergic output and ameliorate depressive behaviors.

On a molecular level, habenula dysfunction in MDD involves alterations in glutamatergic and GABAergic signaling, as well as changes in intracellular calcium dynamics regulating neuronal excitability. Dysregulated expression of receptors such as NMDA and GABA-A within the habenula circuits may contribute to the aberrant neuronal firing patterns observed in depression models. Understanding these molecular underpinnings is vital for the development of pharmacological agents aimed at restoring habenula homeostasis.

Another emerging avenue is the role of neuroinflammation and oxidative stress within the habenula in the pathophysiology of MDD. Evidence suggests that inflammatory cytokines and reactive oxygen species can disrupt habenula synaptic plasticity and neurotransmitter release. Therapeutics reducing inflammation may thereby exert antidepressant effects by normalizing habenula function.

Genetic and epigenetic studies are also beginning to shed light on habenula-related vulnerabilities to depression. Specific gene variants influencing neurotransmitter metabolism and synaptic regulation within this region may predispose individuals to habenular dysregulation under stress. Furthermore, early-life adversity may epigenetically modulate habenula gene expression, sensitizing this circuit to later depressive episodes.

From a behavioral neuroscience perspective, the habenula orchestrates adaptive responses to aversive stimuli, including social defeat and learned helplessness, paradigms closely linked to depression phenotypes. Aberrant habenula responsivity can lead to maladaptive processing of negative environmental cues, perpetuating the cognitive biases and emotional disturbances characteristic of MDD.

The synthesis of preclinical and clinical data in this field is rapidly expanding our understanding of how the habenula integrates environmental, genetic, and neurochemical factors to influence depression risk and symptomatology. This convergence has pivotal implications for refining diagnostic biomarkers and individualizing treatment strategies integrating precision neuromodulation with targeted pharmacotherapy.

Looking ahead, harnessing cutting-edge technologies such as single-cell transcriptomics, in vivo calcium imaging, and machine learning-based neuroimaging analysis promises unprecedented insights into habenula circuit dynamics and their perturbations in MDD. Such innovations will catalyze the translation of fundamental discoveries into effective clinical interventions, potentially transforming the therapeutic landscape of depression.

In sum, the habenula is ascending from relative obscurity to a central focus in depression research, revealing itself as a key neural substrate mediating mood regulation, cognitive processing, and behavioral responses. Its dysfunction contributes fundamentally to the pathogenesis of major depressive disorder through a complex interplay of neural circuit, molecular, and genetic factors. Continued multidisciplinary investigation holds promise for unlocking novel treatment avenues aimed at this pivotal brain region.

The emerging picture of the habenula’s role in depression challenges conventional paradigms and reinforces the need for a more nuanced neurobiological model integrating this often-overlooked structure. As research progresses, targeting the habenula directly or its associated neurotransmission pathways may offer new hope for patients suffering from refractory depression, a goal that today feels closer than ever.

Subject of Research: The role of the habenula in major depressive disorder, emphasizing recent insights from both preclinical animal studies and human clinical research.

Article Title: The Habenula’s role in major depressive disorder: recent insights from preclinical and human studies.

Article References:
Lin, F., Casmey, K., Codeluppi-Arrowsmith, S.A. et al. The Habenula’s role in major depressive disorder: recent insights from preclinical and human studies. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-03867-0

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41398-026-03867-0