Circuit Therapeutics (United States)

The resting primate brain is traversed by spontaneous functional connectivity patterns that show striking differences between conscious and unconscious states. Transcranial direct current stimulation (tDCS), a non-invasive neuromodulatory technique, can improve signs of consciousness in disorders of consciousness (DOCs); however, can it influence both conscious and unconscious dynamic functional connectivity? We investigated the modulatory effect of prefrontal cortex (PFC) tDCS on brain dynamics in awake and anesthetized non-human primates using functional MRI. In awake macaques receiving either anodal or cathodal tDCS, we found that cathodal stimulation robustly disrupted the repertoire of functional connectivity patterns, increased structure-function correlation (SFC), decreased Shannon entropy, and favored transitions toward anatomically based patterns. Under deep sedation, anodal tDCS significantly altered brain pattern distribution and reduced SFC. The prefrontal stimulation also modified dynamic connectivity arrangements typically associated with consciousness and unconsciousness. Our findings offer compelling evidence that PFC tDCS induces striking modifications in the fMRI-based dynamic organization of the brain across different states of consciousness. This study contributes to an enhanced understanding of tDCS neuromodulation mechanisms and has important clinical implications for DOCs.

Post-stroke pain (PSP) affects nearly half of stroke survivors, severely compromising quality of life. The causes of PSP remain underexplored, although there is likely a complex interplay of lesion effects, psychological factors and mobility that play a role in the development of PSP. The aim of the study was to investigate clinical characteristics associated with PSP, as well as structural and functional correlates of PSP using lesion symptom (LSM) and network mapping (LNM). We analyzed data from the INSPiRE-TMS cohort, encompassing 1,022 minor ischemic stroke patients. Pain severity and psychological factors (EQ5D-3L questionnaire) were assessed annually for up to 3 years. In a sub-group of 391 patients with available imaging data, LSM and LNM analyses were conducted to identify neural correlates of PSP. Overall, 47% of patients reported pain 1-year post-stroke. Multivariable regression analyses identified baseline anxiety as being associated with PSP assessed at 1-year post-stroke (OR 2.90, 95% CI 1.17-7.17, p=0.021). LSM did not identify any voxels associated with new severe pain. LNM identified a network involving anterior cingulate cortex, thalamus and insular cortex. Adjusting for anxiety highlighted distinct network contributions, suggesting interactive effects of psychological states on pain perception. Automated comparison to large metanalytical findings using Neurosynth associated the terms 'pain' and 'nociception' most strongly to the identified network. PSP is closely associated with psychological factors such as anxiety. LNM of PSP revealed disruptions in a pain-related neural network consistent with prior pain research. These results warrant external validation and could guide future network-targeted neuromodulation therapies. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01586702 .

Abstract Status epilepticus (SE) has long been linked to neuronal damage in experimental and animal studies, yet direct human evidence remains scarce. The risk of seizure-induced brain injury is central to the definition, urgency, treatment, and prognosis of SE. We studied 2,055 longitudinal MRI scans from 559 individuals, including 33 patients with new-onset refractory SE (NORSE) across multiple centres, to quantify grey matter volume changes during and after SE. We demonstrate a rapid, widespread, and irreversible decline in grey matter volume during NORSE, exceeding normal aging by 80-fold and Alzheimer’s disease by 20-fold. Fluid biomarkers confirmed marked neurodegeneration during NORSE, correlated with grey matter volume reduction, and returned to low levels after SE. Accelerated atrophy was linked to longer SE duration, poorer long-term outcome, and cryptogenic aetiology. These findings underscore the urgency of treating SE to limit brain damage and provide a framework for evaluating potentially neuroprotective interventions in humans.

Genital herpes, caused primarily by herpes simplex virus-2 (HSV-2), remains a highly prevalent sexually transmitted infection with no available vaccine. Previous intramuscular vaccination strategies have failed to protect against HSV-2 infections due to their inability to induce robust local immunity and activate resident memory T cells (Trm cells). The approach known as "prime and pull", whereby host animals are primed with vaccines intramuscularly followed by vaginal delivery of specific chemokines to facilitate the recruitment of effector T cells (i.e., "pull"), confers partial protection against genital HSV-2 disease. However, this strategy fails to prevent infection or establish B cell-mediated immunity. Here, we introduce Bioactive Enhanced Adjuvant Chemokine Oligonucleotide Nanoparticles (BEACONs) formed via electrostatic interactions between CpG DNA and the chemokine CXCL9. This dual-function adjuvant promotes CD8+ T cell recruitment and enhances innate immune activation while reducing non-specific local inflammation. When co-administered vaginally with HSV-2 glycoproteins following intramuscular priming, BEACONs significantly improved protection against HSV by increasing local CD8+ Trm populations and augmenting mucosal IgG and IgA responses. Optimal immune protection required delivery of both local antigen and adjuvant delivery, as neither intramuscular boosting nor introduction of the vaginal adjuvant alone conferred comparable efficacy. Moreover, CD8+ T cell or B cell depletion led to a significant reduction in immune protection conferred by the BEACON-based "pull" strategy. Collectively, these findings highlight the potential of engineered mucosal adjuvants as a means to coordinate local T and B cell responses and offer a promising approach for vaccines targeting genital herpes and other sexually transmitted infections.

Transcranial Magnetic Stimulation (TMS) is rapidly developing as a therapeutic tool for multiple psychiatric disorders. All current FDA-cleared TMS indications for psychiatric illness target the frontal lobes. Historically, TMS target selection was based on reports of brain lesion locations that cause illness or functional neuroimaging correlates within the prefrontal cortex. In addition to prefrontal targets, however, these neuroimaging studies have also consistently implicated posterior brain regions in a variety of psychiatric disorders. To date, these posterior regions have rarely been tested in TMS clinical trials. In this perspective, we consider the role of posterior regions in psychiatric disorders such as the occipital cortex, precuneus, inferior parietal lobules (IPL), and cerebellum. We synthesize preliminary evidence across few existing TMS trials targeting posterior regions and consider the risks and benefits of stimulating posterior targets for the treatment of psychiatric illness.

Functional and somatic symptoms with no detectable structural abnormalities are a common cause of disability. These symptoms are widely believed to have neuropsychiatric origins, and thus may respond to network-targeted brain stimulation. To derive a network-based target, we studied functional and somatic disability after focal brain lesions. Using a normative human connectome database (n=1000), we mapped the circuitry functionally connected to lesions that selectively influence such symptoms in two datasets. First, in ischemic stroke (n=101), we mapped a network causally associated with self-reported functional disability, independent of individual measures of disability. In an independent sample with penetrating head trauma (n=181), lesions connected to our network were associated with greater somatic concern (p=0.001). Across both datasets, functional and somatic symptoms were most associated with lesions connected to the orbitofrontal cortex (pFWE<0.01) and dorsal anterior cingulate, which we propose as potential brain stimulation targets.

Meditation is an accessible mental practice associated with emotional regulation and well-being. Loving-kindness meditation (LKM), a specific subtype of meditative practice, involves focusing one's attention on thoughts of well-being for oneself and others. Meditation has been proven to be beneficial in a variety of settings, including therapeutic applications, but the neural activity underlying meditative practices and their positive effects are not well understood. It has been difficult to understand the contribution of deep limbic structures given the difficulty of studying neural activity directly in the human brain. Here, we leverage a unique patient population, epilepsy patients chronically implanted with responsive neurostimulation devices that allow chronic, invasive electrophysiology recording to investigate the physiological correlates of LKM in the amygdala and hippocampus of novice meditators. We find that LKM-associated changes in physiological activity were specific to periodic, but not aperiodic, features of neural activity. LKM was associated with an increase in γ (30 to 55 Hz) power and an alternation in the duration of β (13 to 30 Hz) and γ oscillatory bursts in both the amygdala and hippocampus, two regions associated with mood disorders. These findings reveal the nature of LKM-induced modulation of limbic activity in first-time meditators.