The centerpiece of the October issue of The American Journal of Psychiatry is a special issue on neuromodulation and precision therapeutics, assembled with guest editor William McDonald, M.D., professor of psychiatry and behavioral sciences at Emory University School of Medicine. McDonald joins Ned Kalin, the journal’s editor-in-chief, on this month’s AJP Audio podcast to discuss the collection. The special issue arrives at a moment when neuromodulation, once a niche corner of psychiatry, has become one of its most active frontiers, encompassing transcranial magnetic stimulation, electroconvulsive therapy, vagus nerve stimulation, and emerging techniques that promise to steer electrical activity in deep brain circuits without surgery.

One of the issue’s framing contributions describes the current wave of brain stimulation therapeutic interventions in neuropsychiatry as a Cambrian explosion, an evocative metaphor borrowed from evolutionary biology to convey the sheer diversity of approaches now proliferating. Alongside it, a second perspective article examines artificial intelligence as the computational framework for adaptive closed-loop neuromodulation in psychiatry. Closed-loop systems, which sense neural activity and adjust stimulation parameters in real time, are widely viewed as the next step beyond fixed-protocol stimulation, and the article argues that machine learning provides the mathematical machinery needed to make such adaptive control clinically reliable.

The special issue also features original clinical trials that test whether precision targeting can improve outcomes. One randomized, sham-controlled trial investigates bilateral theta-burst stimulation of dorsolateral prefrontal cortex regions for late-life depression, a population in which treatment-resistant mood disorders carry substantial disability and medical burden. A companion study reports convergent network localization of brain stimulation targets for trait anxiety, an approach that uses converging evidence about brain networks to identify where stimulation might most effectively modulate a given symptom dimension. AJP Deputy Editor Daniel Pine, M.D., highlights both studies in accompanying videos for the journal’s readership.

Two further trials push the precision theme further. The first, the CORRECT-BD trial, compares clinical and cognitive outcomes of right unilateral ultrabrief electroconvulsive therapy against magnetic seizure therapy for bipolar depression, a comparison that speaks directly to a longstanding clinical concern: preserving cognition while retaining the robust antidepressant efficacy of seizure-based treatments. The second is an individualized, connectivity-guided versus conventional targeting trial of accelerated theta-burst stimulation in depression, a randomized, double-blind, parallel-design study that asks whether personalizing stimulation targets to each patient’s brain connectivity outperforms standard coordinate-based targeting.

The issue also revisits one of the most consequential and debated studies in the field. The RECOVER trial of vagus nerve stimulation in markedly treatment-resistant depression is examined in an article on its critical findings, lessons learned, and future directions, with lead author Charles R. Conway, M.D., discussing the results on the AJP Audio podcast. Additional contributions survey precision neuromodulation with a focus on temporal interference stimulation, a technique designed to reach deep brain structures noninvasively by interfering two high-frequency fields at a targeted point. A commentary argues for advancing brain stimulation toward first-line psychiatric therapy through wearable disposable electrotherapy, while another article addresses implantable neuromodulation devices in psychiatry, weighing human fidelity and the implementation challenges that stand between promising devices and routine clinical use.

The October issue of Psychiatric Services shifts the lens from circuits to systems, publishing research on how mental health care is organized, measured, and delivered. Highlights include the Mental Wellness Tool, a brief screener designed to detect mental disorders, substance use disorders, and suicide risk in a single instrument, and a set of recommendations from a participatory policymaking symposium on emergency psychiatric evaluation of people under arrest, an area where clinical practice, law enforcement, and civil rights intersect. Other articles examine VA health care utilization among U.S. veterans through the influence of social determinants of health, and a methodological piece on suicide surveillance and Simpson’s Paradox warns that aggregating data can obscure critical patterns that appear only when populations are disaggregated.

Access and equity questions recur throughout the issue. One study documents wait times and documentation requirements for child psychiatric care across payer and facility types, quantifying the administrative friction families face when seeking help for children. Another reports on public support for state laws requiring addiction programs to offer FDA-approved medications for opioid use disorder, a finding with direct relevance to ongoing policy debates about whether treatment programs should be legally obligated to provide evidence-based pharmacotherapy. Together, these papers illustrate how service-level research complements clinical neuroscience by identifying where the system itself becomes a barrier to care.

The American Journal of Psychotherapy contributes a third perspective, centered on the human relationship at the heart of psychiatric treatment. Articles examine gender and age differences in psychotherapy use among U.S. adults with depression and anxiety, and explore the effects of psychotherapies for posttraumatic stress disorder on anger, an often-overlooked symptom in trauma treatment research. Clinical technique is addressed in a paper on the RFP-C triangle of conflict, which considers how attending to countertransference can help clinicians listen more effectively to children with disruptive behaviors. Cultural adaptation is the focus of an article on interpersonal psychotherapy in the Chinese cultural context, while a study of group acceptance and commitment therapy for adolescent anxiety reports on initial acceptability and outcomes of a group format aimed at expanding access for young patients.

Psychiatric Research and Clinical Practice rounds out the collection with translational and real-world studies. A viewpoint article considers fostering social connection, tracing progress and opportunities within the VA and beyond, a topic of growing public health interest given evidence linking isolation to morbidity. A comparative study assesses the risks of pregnancy complications in women prescribed psychostimulants or atomoxetine during pregnancy following pre-pregnancy stimulant use, addressing a population long underrepresented in psychopharmacology research. The journal also publishes a real-world effectiveness and cost-differential analysis of intranasal esketamine versus intramuscular ketamine, two rapid-acting treatments for depression whose relative value outside controlled trials remains a pressing question for clinicians and payers. Finally, a real-world pilot evaluates the collaborative care model for adults with cognitive impairment and neuropsychiatric symptoms in primary care, testing whether an integrated care framework developed for depression can extend to patients with complex neuropsychiatric needs. Journalists seeking access to the publications can contact the American Psychiatric Association press office at press@psych.org.

Subject of Research: Neuromodulation, precision therapeutics, esketamine, and mental health services research featured across APA journals

Article Title: October 2026 Issues of APA Journals feature new research on neuromodulation and precision therapeutics, esketamine, and more

Article References: October 2026 Issues of APA Journals feature new research on neuromodulation and precision therapeutics, esketamine, and more. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: neuromodulation, precision therapeutics, brain stimulation, esketamine, theta-burst stimulation, vagus nerve stimulation, electroconvulsive therapy, depression, psychotherapy, psychiatric services, American Psychiatric Association, mental health care

The team’s strategy began with forward genetics in the nematode Caenorhabditis elegans, a workhorse of developmental biology whose translucent body and well-mapped nervous system make it ideal for visualizing cellular defects. The researchers focused on two ciliary tubulins, TBA-5 and TBB-4, which are the worm counterparts of human tubulins implicated in ciliopathy. Worms carrying the tba-5(A19V) or tbb-4(L253F) mutations show defective sensory cilia, structures whose axonemal microtubules depend on precisely assembled tubulin. Ciliary failure can be scored conveniently through a dye-filling assay, because animals with broken cilia cannot take up fluorescent lipophilic dyes. Using ethyl methanesulfonate mutagenesis to sprinkle random point mutations across the genome, the team screened thousands of progeny for animals in which ciliary function re-emerged despite the presence of the toxic allele. This classic suppressor-screening logic—mutate at random, then ask which second-site changes rescue the phenotype—allowed the investigators to let evolution reveal the rules of tubulin suppression rather than guessing at them in advance.

The screen was remarkably productive, and its output fell into three functionally distinct classes of tubulin-autonomous missense suppressors. The most medically interesting category proved to be intergenic suppressors: missense variants arising not in the mutant gene itself but in the reciprocal partner tubulin. Because microtubules are obligate heteropolymers of α- and β-tubulin, a compensating change in the partner chain can, in principle, rebalance the assembly system. Two mechanistic subtypes emerged among these intergenic suppressors. The first, designated Sup I, consists of assembly-defective variants that rescue through competitive exclusion. These mutant partner tubulins bind the toxic tubulin in nonproductive heterodimers, sequestering it and preventing it from co-polymerizing into filaments, thereby protecting the pool of wild-type tubulin that remains free to assemble a normal microtubule network. Crucially, the team showed that this is a genuine gain-of-function effect: loss-of-function null alleles of the same gene could not achieve the rescue, and the suppressive variants specifically blocked incorporation of the pathogenic tubulin into microtubules in transfected cells.

The second and third classes, Sup II and Sup III, act through an entirely different principle. These are assembly-competent variants that themselves incorporate into microtubules alongside the diseased tubulin and modulate filament dynamics in a way that counteracts the mutation’s effect. Rather than removing the poison, they dilute and stabilize it from within, restoring the delicate balance of growth and shrinkage—dynamic instability—that healthy microtubules must maintain. The authors demonstrated these mechanisms in human cells, using HeLa cell lines engineered with split-GFP and epitope-tagged tubulin constructs to visualize how disease variants such as TUBA4A(E284G) and TUBB8(V229A) shatter the microtubule network, and how co-expressed suppressor variants from the reciprocal isotype family rebuild it. Pull-down assays with tagged constructs confirmed that both classes of suppressor form heterodimers with the pathogenic tubulins, yet their consequences for the polymer differ sharply: competitive exclusion in one case, dynamic rescue in the other.

Perhaps the most striking finding is the conservation of these mechanisms across evolutionary distance. Selected intergenic suppressors identified in worms were transplanted into human cells and rescued pathogenic tubulin-induced microtubule defects there as well. More ambitiously, the team moved into murine oocytes, where the β-tubulin isotype TUBB8 dominates the meiotic spindle and mutations in TUBB8 are a known cause of human oocyte maturation arrest and female infertility. In oocytes carrying tubulinopathy-related tubulin variants, the Sup III class of assembly-competent suppressors rescued meiotic spindle defects, outperforming supplementation with wild-type tubulin itself. This result carries a conceptual punch: simply adding more of the normal protein is not the best way to counter a dominant-negative poison, whereas a rationally chosen gain-of-function variant can outperform the wild type. It suggests that for dominant disorders, the therapeutic goal should not merely be replacement but active suppression tuned to the specific biophysical lesion caused by each patient mutation.

To understand how assembly-competent suppressors work at the molecular level, the researchers conducted a systematic mutational analysis of TUBA1A, the human α-tubulin most frequently implicated in cortical malformations. By mapping a landscape of variants capable of rescuing pathogenic β-tubulin mutants, they defined a cohort of gain-of-function, assembly-competent suppressors scattered across the tubulin sequence. Molecular dynamics simulations then illuminated the physical basis of the rescue. Microtubules are built from protofilaments—longitudinal strings of tubulin dimers that associate laterally to form the tube—and their geometry is exquisitely sensitive to the conformation of each subunit. Pathogenic mutations distort this geometry, bending protofilaments away from the correct lattice curvature and destabilizing the growing tip. The simulations showed that compensating suppressor mutations restore protofilament geometry, re-establishing the distances and contacts, including those near the GTP-binding pocket, that allow the lattice to close properly and dynamic instability to proceed normally.

The technical infrastructure behind the study is as noteworthy as its biological conclusions. The team employed AlphaFold-guided engineering of split-GFP technology to label endogenous tubulins without perturbing their function, allowing them to track incorporation of specific variants into cellular microtubule networks with high fidelity. Deep learning-based phenotypic classification accelerated the scoring of cellular rescue, and total internal reflection fluorescence microscopy captured in vitro microtubule dynamics in real time, showing directly that suppressor variants restore the growth and shrinkage behavior of individual filaments disrupted by pathogenic tubulins. Molecular dynamics trajectories, run for extended timescales on model protofilaments composed of TUBA1A and TUBB8, were deposited in public repositories alongside custom analysis code, reflecting a commitment to transparency that other labs can build upon.

The medical implications are considerable, though the authors are careful to frame the work as a foundation rather than a therapy. Tubulinopathies are genetically heterogeneous, with pathogenic variants across multiple α- and β-tubulin genes producing overlapping but distinct clinical spectra, and current management is largely supportive. A framework that maps which suppressor variants neutralize which pathogenic mutations—and defines the structural logic connecting sequence change to microtubule mechanics—opens a path toward what the authors describe as precision therapeutics for dominant tubulinopathies. In principle, allele-specific suppressors could be delivered through gene therapy vectors to neurons or other affected tissues, a strategy conceptually similar to suppressor-based approaches now being explored for other dominant-negative diseases such as certain dystrophies and neurodegenerative conditions. The demonstration that engineered suppressors outperform wild-type supplementation in oocytes is particularly encouraging for reproductive medicine, where TUBB8-related infertility currently offers few options.

There are, of course, substantial distances between a rescue in a HeLa cell or a mouse oocyte and a treatment for a child with lissencephaly. Delivery to the developing brain, dosage control, immune considerations and the risk that suppressor variants themselves perturb microtubule function in unanticipated ways all remain open questions, and the study’s own data show that different suppressor classes suit different mutational contexts. Yet the conceptual advance is unambiguous. By converting a devastating class of dominant mutations into an addressable engineering problem—and by showing that the solution generalizes from nematode cilia to human cells to mammalian oocytes—Xu, Guo and colleagues have transformed how the field can think about tubulinopathies. The humble suppressor screen, one of the oldest tools in genetics, has once again delivered insights that no amount of pure structural prediction could have supplied, and in doing so it has sketched the outline of a rational therapeutic playbook for disorders long considered untreatable at their molecular root.

Subject of Research: Gain-of-function tubulin suppressor variants that restore microtubule dynamics in dominant-negative tubulinopathies

Article Title: Gain-of-function suppressors restore microtubule dynamics and rescue dominant-negative tubulinopathies

Article References: Xu, K., Guo, Z., Ke, J., Chen, Z., Mao, L., Sun, R., Chen, M., Na, J., Xie, S., Zhou, T., Zhang, J., Wang, H., Shi, S.-H., Li, W., & Ou, G. (2026). Gain-of-function suppressors restore microtubule dynamics and rescue dominant-negative tubulinopathies. Nature Cell Biology. https://doi.org/10.1038/s41556-026-02066-9

Image Credits: AI Generated

DOI: 10.1038/s41556-026-02066-9

Keywords: tubulinopathies, microtubules, tubulin, TUBA1A, suppressor screen, Caenorhabditis elegans, dominant-negative mutation, gain-of-function, molecular dynamics simulation, cilia, genetic rescue, precision therapeutics