The research team mined the Web of Science Core Collection, running a structured query that paired every variant of “obsessive-compulsive disorder” with a battery of imaging terms spanning MRI, functional and structural MRI, diffusion tensor imaging, electroencephalography, event-related potentials, and positron emission tomography. The raw search returned 2,211 records, which the researchers filtered down to 2,000 English-language articles and reviews dated from January 1, 2000 to December 31, 2024. They then applied two widely used network-mapping programs: CiteSpace, developed by Chaomei Chen, which detects emerging trends, hotspots, and citation bursts, and VOSviewer, a Java-based tool created by Nees Jan van Eck and colleagues in 2010 that visualizes co-authorship, co-citation, and keyword co-occurrence networks. Author-supplied keywords were standardized to merge synonyms — “fMRI” and “functional magnetic resonance imaging,” for example — and only terms appearing at least 15 times across the corpus entered the final co-occurrence network, a threshold chosen empirically to keep the maps interpretable while preserving meaningful themes.

The output curves tell a story of relentless growth. Publication volume and citation frequency climbed in a fluctuating upward trajectory before peaking in 2021, when the field produced 155 papers that accumulated 8,457 citations in a single year. Although output dipped slightly after 2021, citation efficiency stayed remarkably high: in several years — 2015, 2017, and every year from 2021 through 2024 — the citation-to-publication ratio exceeded 50, indicating sustained high average impact per article. Crucially, the years of highest productivity, from 2019 to 2022, did not come at the cost of influence, since elevated citation ratios persisted throughout the expansion. To formalize the trajectory, the team fitted a sixth-order polynomial regression to the cumulative data, achieving a goodness-of-fit coefficient of R² = 0.9997 — an almost perfect fit suggesting the field remains in a phase of vigorous development and will keep attracting researchers for the foreseeable future.

Beneath the growth curve, the analysis documents a profound conceptual migration. In the early years, keywords like “glucose metabolic rates” and “symptom provocation” burned brightest, sustaining citation bursts from 2000 to 2013 — echoes of the PET studies from the late 1980s that first linked OCD to metabolic abnormalities in cortico-striatal pathways. “Cerebral blood flow” registered the single most intense burst in the dataset, with a burst strength of 24.31, followed by “glucose metabolic rates” at 21.08 and “positron emission tomography” at 20.82. Then the ground shifted. The arrival of functional MRI and diffusion tensor imaging moved the field from isolated regional measurements toward whole-network analyses of the cortico-striato-thalamo-cortical loops long implicated in the disorder. “fMRI” appeared as a keyword 230 times and “functional connectivity” 72 times, while a newer cluster of terms — “voxel-based morphometry,” “regional homogeneity,” and “resting-state fMRI” — garnered significant attention only in recent years, marking the current frontier from psychological and neuroscientific perspectives.

The most-cited papers recapitulate this intellectual evolution. At the top sits a 2002 study by van Veen and Carter, “The anterior cingulate as a conflict monitor: fMRI and ERP studies,” which used functional MRI and event-related potentials to cast the anterior cingulate cortex as the brain’s cognitive-conflict detector. Second, with 941 citations, is the 2015 JAMA Psychiatry meta-analysis by Goodkind and colleagues, which identified a common neurobiological substrate for mental illness: gray-matter reductions in the dorsal anterior cingulate cortex and bilateral insula shared across schizophrenia, bipolar disorder, depression, addiction, OCD, and anxiety. Third, with 874 citations, is Menzies and colleagues’ 2008 review revisiting the orbitofronto-striatal model of OCD — a paper whose citation burst strength of 55.56 was the highest in the entire 25-year record. Structural findings have since crystallized through the ENIGMA consortium’s mega-analyses: increased gray matter volume in the thalamus and striatum, reductions in the medial prefrontal and anterior cingulate cortex, and convergent multimodal abnormalities centered on the insula as a central node of pathophysiology.

But the atlas of OCD neuroimaging has a pronounced geographic tilt. The United States led all countries with 729 articles — 36.5 percent of global output — and 40,208 citations, far outpacing the United Kingdom’s 223 papers and 16,689 citations, Germany’s 237 papers, China’s 265 papers, and Canada’s 161. China’s rise is striking, as it now ranks second in volume, yet its institutions entered deep international collaboration only after 2015, hinting at persistent barriers in knowledge exchange. More troubling, low- and middle-income countries, where lifetime OCD prevalence of 2 to 3 percent matches that of richer nations, remain largely absent from the literature despite a comparable disease burden. Brazil stands out as an instructive exception: the University of São Paulo, though modest in output, achieved relatively high citation counts through strategic partnerships with North American and European laboratories. The authors warn that findings drawn almost exclusively from high-income populations may not generalize across the genetic, environmental, and sociocultural contexts that shape how the disorder manifests worldwide.

The analysis also maps the people and places steering the science. Jun Soo Kwon of Seoul National University in South Korea tops productivity with 52 papers, while Odile A. Van Den Heuvel of the Netherlands ranks second with 43 publications and the highest total link strength in the field — a score of 162 reflecting her extensive international collaborations. Author networks cluster tightly around institutions: a Seoul-centered group around Kwon, a Barcelona group around Carles Soriano-Mas, an Amsterdam cluster including Dick J. Veltman, a Harvard-Brown group anchored by Scott L. Rauch and Sabine Wilhelm, and a Michigan-centric cluster tied to the OCD Foundation Genetics Consortium. King’s College London leads institutional output with 70 papers, followed by Harvard University with 67 and Massachusetts General Hospital with 54, while Yale University — birthplace of the Yale-Brown Obsessive Compulsive Scale and early SSRI trials — holds 51 papers and 6,435 citations. Notably, the Chinese and South Korean institutional clusters remain geographically self-contained, collaborating mostly within their own borders.

Where the science is published matters as much as who produces it. Psychiatry Research-Neuroimaging led all journals with 82 OCD neuroimaging papers, trailed by Biological Psychiatry and Frontiers in Psychiatry with 58 each and the Journal of Affective Disorders with 55. Citation gravity, however, concentrated in the flagship psychiatry venues: Archives of General Psychiatry accumulated 5,523 citations, Biological Psychiatry 5,435, Neuroimage 4,827, and the American Journal of Psychiatry 4,236. The analysis exposes a visibility paradox — specialized outlets like the Journal of Obsessive-Compulsive and Related Disorders, with an impact factor of 1.9 and a Q3 quartile ranking, publish deeply focused OCD work yet struggle for attention, while broad-scope journals with impact factors reaching 15.1 absorb the field’s most-cited findings. A dual-map overlay of journal citations showed journals focusing on molecular biology and on psychology, education, and health citing psychology-and-social-science venues more heavily than molecular-biology-and-genetics journals, a signature of the field’s cross-disciplinary traffic, with journals like NEUROCOMPUTING emerging as bridges between artificial intelligence and clinical neuroscience.

Looking forward, the keyword and citation-burst data point to two converging frontiers. The first is neuromodulation: “deep brain stimulation” appeared 86 times, linked chiefly to clinical trials targeting the anterior limb of the internal capsule in treatment-resistant patients, including a randomized, double-blind, sham-controlled trial of stimulation at the bed nucleus of the stria terminalis. Yet a scoping review identified only 13 deep brain stimulation trials in pediatric populations — a glaring gap for a disorder that so often begins in childhood. The second frontier is transdiagnostic: rather than treating OCD as an isolated circuit dysfunction, researchers are mapping shared mechanisms such as cognitive inflexibility and aberrant threat processing across diagnostic boundaries, following evidence that frontoparietal control-network disruptions recur in attention-deficit/hyperactivity disorder and major depressive disorder alike, while salience-network abnormalities span multiple anxiety-related conditions. Machine learning is accelerating both trends — the ENIGMA OCD working group recently analyzed white-matter diffusion patterns across 1,653 individuals, and specific resting-state fMRI parameters have demonstrated predictive value for individual clinical outcomes.

The analysis ends on a cautionary note about reproducibility. Only 5 percent of the studies examined made raw imaging data available, and variability in fMRI preprocessing pipelines — particularly motion-correction strategies for resting-state scans — continues to complicate comparisons across laboratories. The authors argue that the path forward runs through open science: federated learning platforms that allow multi-site analysis without moving patient data, as the ENIGMA-OCD consortium already practices; standardized acquisition and analysis protocols endorsed by journals and professional organizations; mandatory data sharing through repositories like OpenNeuro; and deliberately designed consortia that include low- and middle-income sites from inception, drawing inspiration from initiatives like the NIH’s Fogarty International Center. Add longitudinal pediatric cohorts tracking neurodevelopment and generative AI models capable of simulating OCD circuitry and forecasting treatment response, the researchers say, and the field could finally deliver what 25 years of imaging has promised: biomarkers and therapies that work not just in Boston, London, or Seoul, but everywhere the disorder occurs.

At the heart of this research lies the striatum, a critical subcortical brain region implicated in habit formation, reward processing, and motor control. Historically, the striatum’s involvement in OCD has been suspected due to its functional connections within cortico-striatal-thalamo-cortical (CSTC) loops, which are theorized to mediate the intrusive thoughts and repetitive behaviors hallmarking the disorder. However, the molecular and functional signatures defining striatal dysfunction in OCD patients had remained largely speculative prior to this study. The investigators broke new ground by integrating transcriptomic data—detailing gene expression profiles—with longitudinal functional magnetic resonance imaging (fMRI), enabling a spatiotemporal dissection of striatal anomalies from a molecular to a network level.

The study enrolled a cohort of drug-naive individuals diagnosed with OCD alongside matched healthy controls, employing whole-brain functional scans conducted at multiple time points. This longitudinal approach allowed the researchers to capture dynamic changes in neural activity patterns and connectivity within the striatum and related circuits over time. By concurrently profiling the striatal transcriptome—a comprehensive catalog of gene expression within this region—the team unveiled a striking convergence between dysregulated molecular pathways and aberrant brain function. Notably, the perturbations observed were intrinsic to the OCD state, not secondary to medication or chronic illness effects.

Among the most significant molecular findings was the altered expression of genes involved in synaptic transmission and neuroplasticity. These alterations suggest that synaptic efficacy within the striatum might be compromised in OCD, potentially leading to the persistence of maladaptive neural loops underpinning compulsive behaviors. Intriguingly, the expression profiles also highlighted immune-related pathways, echoing emerging evidence that neuroinflammation could contribute to psychiatric pathophysiology. This molecular fingerprint provides a tangible link connecting striatal dysfunction to the phenomenology of OCD at a cellular level.

Functionally, the fMRI data illuminated aberrant connectivity patterns between the striatum and prefrontal cortical areas responsible for executive control and decision-making. Disrupted communication between these regions may underlie the hallmark inability in OCD patients to suppress intrusive thoughts and inhibit compulsive actions. The longitudinal scans revealed that these network abnormalities are not static; instead, they exhibit fluctuations potentially reflective of symptom severity or compensatory mechanisms evolving over the course of the disorder.

The integration of transcriptomic and imaging data represents a novel methodological leap forward. By combining molecular signatures with functional readouts, the research offers a multidimensional portrait of OCD pathophysiology. This approach transcends prior studies that examined either genomics or neuroimaging in isolation, thereby deepening our understanding of how gene expression abnormalities translate into circuit-level dysfunctions within the brain. Importantly, the findings hold translational promise, suggesting potential biomarkers for early diagnosis and targets for intervention.

The focus on drug-naive patients is critical, as psychotropic medications frequently modulate both gene expression and neural activity, confounding attempts to pinpoint disease-specific mechanisms. By avoiding this variable, the study achieves a clearer depiction of baseline abnormalities inherent to OCD. This clarity enhances confidence that the observed molecular and functional signatures are fundamental to the disorder’s neuropathology rather than artifacts of treatment.

Moreover, the temporal dimension offered by longitudinal fMRI scans captures the evolution of striatal dysregulation over time, thereby informing models of disease progression. Such insights could shape future efforts to tailor therapeutic timing and strategies, emphasizing the windows during which interventions might most effectively recalibrate dysfunctional networks or molecular pathways. In this vein, the study also raises important questions about whether pharmacological or behavioral therapies might normalize these signatures and how such effects could be monitored.

The discovery of immune-related gene involvement aligns with a growing paradigm shift recognizing inflammation as a contributor to psychiatric conditions. While traditionally psychiatric disorders were viewed largely through a neurochemical lens, the recognition of immunological processes introduces novel mechanistic layers and potential avenues for treatment, such as anti-inflammatory agents. The striatum’s apparent immunogenomic alterations might thus represent a convergence point between neuropsychiatric and systemic immune processes.

Another fascinating aspect uncovered was the heterogeneity of striatal dysfunction among patients, hinting at OCD’s underlying biological complexity. Variability in gene expression profiles and functional connectivity patterns suggests the presence of distinct molecular subtypes or endophenotypes within OCD. This insight fuels the precision medicine ambition of categorizing patients based on neural signatures to customize treatment regimens optimally.

The study’s findings reinforce the conceptualization of OCD as a circuit-based disorder with a biological basis grounded in specific brain regions. This contrasts with outdated notions relegating OCD symptoms to purely psychological realms. By substantiating objective biomarkers, the research advances the legitimacy of OCD as a neurobiological illness, which may reduce stigma and encourage the development of novel diagnostic tools.

Technologically, the research leveraged state-of-the-art transcriptome sequencing and sophisticated fMRI analytic frameworks capable of resolving functional relationships at high resolution. The synergy between molecular biology and neuroimaging exemplifies the power of interdisciplinary collaboration in tackling complex psychiatric disorders. Future studies building on this foundation may incorporate additional modalities such as PET imaging or single-cell sequencing to dissect the striatum’s microenvironment further.

Critically, the study raises potential implications for drug development. By identifying key molecular pathways associated with striatal dysfunction, pharmaceutical efforts might focus on modulating synaptic plasticity or neuroimmune interactions specific to the disorder’s neural locus. This targeted approach contrasts with broad-spectrum treatments and promises to enhance therapeutic efficacy while minimizing side effects.

The research team also discussed the potential for these integrated biomarkers to serve as outcome measures in clinical trials. Objective readouts combining gene expression and neural activity could provide a more sensitive gauge of treatment response than subjective scales. Such measures would accelerate the pipeline from bench to bedside, facilitating the evaluation of novel interventions and personalized treatment paradigms.

In conclusion, this seminal study ushers in a new era of psychiatric research by decoding the striatum’s role in OCD through a compelling synthesis of transcriptomic and longitudinal neuroimaging data. Its insights pave the way for a deeper mechanistic understanding and foster optimism that more precise and effective therapies are on the horizon. As the field moves forward, leveraging such multidimensional approaches will be key to unraveling the complexities not only of OCD but of mental health disorders broadly.

Subject of Research: Obsessive-compulsive disorder; striatal dysfunction; transcriptomics; longitudinal functional magnetic resonance imaging.

Article Title: Decoding the striatum of drug-naive patients with obsessive-compulsive disorder: a transcriptome and longitudinal functional magnetic resonance imaging study.

Article References:
Han, Y., Yan, H., Shan, X. et al. Decoding the striatum of drug-naive patients with obsessive-compulsive disorder: a transcriptome and longitudinal functional magnetic resonance imaging study. Transl Psychiatry 15, 258 (2025). https://doi.org/10.1038/s41398-025-03475-4

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41398-025-03475-4