Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes (‘biotypes’) defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82–93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.

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Background Repetitive transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for depression, but its underlying mechanism of action remains unknown. Abnormalities in two large-scale neuronal networks—the frontoparietal central executive network (CEN) and the medial prefrontal-medial parietal default mode network (DMN)—are consistent findings in depression and potential therapeutic targets for TMS. Here, we assessed the impact of TMS on activity in these networks and their relation to treatment response. Methods We used resting state functional magnetic resonance imaging (rs-fMRI) to measure functional connectivity within and between the DMN and CEN in 17 depressed patients, before and after a five-week course of TMS. Motivated by prior reports, we focused on connectivity seeded from the DLPFC and the subgenual cingulate, a key region closely aligned with the DMN in depression. Connectivity was also compared to a cohort of 35 healthy controls. Results Prior to treatment, functional connectivity in depressed patients was abnormally elevated within the DMN and diminished within the CEN, and connectivity between these two networks was altered. TMS normalized depression-related subgenual hyperconnectivity in the DMN but did not alter connectivity in the CEN. TMS also induced anticorrelated connectivity between the DLPFC and medial prefrontal DMN nodes. Baseline subgenual connectivity predicted subsequent clinical improvement. Conclusions TMS selectively modulates functional connectivity both within and between the CEN and DMN, and modulation of subgenual cingulate connectivity may play an important mechanistic role in alleviating depression. The results also highlight potential neuroimaging biomarkers for predicting treatment response.

Multiple randomized controlled trials and published literature have supported the safety and efficacy of rTMS antidepressant therapy. These consensus recommendations, developed by the NNDC rTMS Task Group and APA CoR Task Force on Novel Biomarkers and Treatments, provide comprehensive information for the safe and effective clinical application of rTMS in the treatment of MDD.

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Oral antibiotics (median, 3.1-4 weeks) and nasal steroids are used >90% of the time by a majority of ARS members for maximal medical treatment of CRS.

IntroductionTranscranial magnetic stimulation (TMS) is an effective treatment for major depressive disorder (MDD), particularly in individuals resistant to first-line antidepressants.1-3 Effect sizes of TMS from recent meta-analyses range from 0.39 to 0.55. 4,5 Less is known about the neurobiological mechanisms of antidepressant response to TMS. Emerging evidence suggests that in addition to its effects on the dorsolateral prefrontal cortex (DLPFC), TMS also affects structures to which the DLPFC projects, including the medial prefrontal cortex (MPFC). 6 The MPFC is overactive in individuals with MDD,7 and functional connectivity between the DLPFC and MPFC predicts response to TMS. [8][9][10] Little is known about how connectivity between the DLPFC and MPFC gives rise to the antidepressant effect of TMS.Other antidepressants appear to act in part by modulating the excitability of cortical circuits. Levels of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, which are generally decreased in depressed individuals, 11 have been reported to increase after treatment with selective serotonin reuptake inhibitors (SSRIs) 12 and electroconvulsive therapy (ECT).13 Although TMS affects the balance of excitation and inhibition in cortical circuits, 14 it is unknown whether changes in excitation-inhibition balance mediate antidepressant response.In this naturalistic study, we tested whether TMS alters the levels of GABA and those of the combined resonance of glutamate and glutamine (Glx) in patients with MDD. Specifically, the standard J-edited spin echo difference proton magnetic resonance spectroscopy ( 1 H MRS) technique was implemented at 3 T to measure levels of MPFC GABA and Background: GABAergic and glutamatergic neurotransmitter systems are central to the pathophysiology of depression and are potential targets of repetitive transcranial magnetic stimulation (rTMS). We assessed the effect of 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) of patients with major depressive disorder on the levels of medial prefrontal cortex (MPFC) γ-aminobutyric acid (GABA) and the combined resonance of glutamate and glutamine (Glx) as assessed in vivo with proton magnetic resonance spectroscopy ( 1 H MRS). Methods: Currently depressed individuals between the ages of 23 and 68 years participated in a 5-week naturalistic, open-label treatment study of rTMS, with 1 H MRS measurements of MPFC GABA and Glx levels at baseline and following 5 weeks of the rTMS intervention. We applied rTMS pulses over the left DLPFC at 10 Hz and 80%-120% of motor threshold for 25 daily sessions, with each session consisting of 3000 pulses. We assessed therapeutic response using the 24-item Hamilton Rating Scale for Depression (HAMD24). The GABA and Glx levels are expressed as ratios of peak areas relative to the area of the synchronously acquired and similarly fitted unsuppressed voxel water signal (W). Results: Twenty-three currently depressed individuals (7 men) participated in the study. GABA/W in the MPFC i...

Functional TLR9 protein is expressed by normal and diseased sinonasal epithelial cells. The level of TLR9 expression is decreased in CRSwNP patients, consistent with the previous finding of decreased TLR9 mRNA in whole sinonasal tissue. These findings suggest that impaired innate immune responses to pathogens via TLR9 on sinonasal epithelial cells may represent a critical mechanism in chronic inflammatory sinus disease.