The combination of intravital microscopy and animal models of disease has propelled studies of disease mechanisms and treatments. However, many disorders afflict tissues inaccessible to light microscopy in live subjects. Here we introduce cellular-level time-lapse imaging deep within the live mammalian brain by one-and two-photon fluorescence microendoscopy over multiple weeks. Bilateral imaging sites allowed longitudinal comparisons within individual subjects, including of normal and diseased tissues. Using this approach we tracked CA1 hippocampal pyramidal neuron dendrites in adult mice, revealing these dendrites' extreme stability (>8,000 day mean lifetime) and rare examples of their structural alterations. To illustrate disease studies, we tracked deep lying gliomas by observing tumor growth, visualizing three-dimensional vasculature structure, and determining microcirculatory speeds. Average erythrocyte speeds in gliomas declined markedly as the disease advanced, notwithstanding significant increases in capillary diameters. Time-lapse microendoscopy will be applicable to studies of numerous disorders, including neurovascular, neurological, cancerous, and trauma-induced conditions.

Subcallosal cingulate cortex deep brain stimulation (SCC-DBS) is an experimental therapy for treatment-resistant depression (TRD). Refinement and optimization of SCC-DBS will benefit from increased study of SCC electrophysiology in context of ongoing high-frequency SCC-DBS therapy. The study objective was a 7-mo observation of frequency-domain 1/ f slope in off-stimulation local field potentials (SCC-LFPs) alongside standardized measurements of depression severity in 4 patients undergoing SCC-DBS. SCC was implanted bilaterally with a combined neurostimulation-LFP recording system. Following a 1-mo off-stimulation postoperative phase with multiple daily recordings, patients received bilateral SCC-DBS therapy (130 Hz, 90 μs) and weekly resting-state SCC-LFP recordings over a 6-mo treatment phase. 1/ f slopes for each time point were estimated via linear regression of log-transformed Welch periodograms. General linear mixed-effects models were constructed to estimate pretreatment sources of 1/ f slope variance, and 95% bootstrap confidence intervals were constructed to estimate treatment phase 1/ f slope association with treatment response (50% decrease in preimplantation symptom severity). Results show the time of recording was a prominent source of pretreatment 1/ f slope variance bilaterally, with increased 1/ f slope magnitude observed during night hours (2300–0659). Increase in right 1/ f slope was observed in the setting of treatment response, with bootstrap analysis supporting this observation in 3 of 4 subjects. We conclude that 1/ f slope can be measured longitudinally in a combined SCC-DBS/LFP recording system and likely conforms to known 1/ f circadian variability. The preliminary evidence of 1/ f slope increase during treatment response suggests a potential utility as a candidate biomarker for ongoing development of adaptive TRD-neuromodulation strategies. NEW & NOTEWORTHY In four patients with treatment-resistant depression undergoing therapeutic deep brain stimulation (DBS), we present the first longitudinal observations of local field potentials (LFP) from the subcallosal cingulate region outside the postoperative period. Specifically, our results demonstrate that frequency-domain 1/ f activity is measurable in a combined DBS-LFP recording system and that right hemisphere recordings appear sensitive to mood state, thus suggesting a potential readout suitable for consideration in ongoing efforts to develop adaptive DBS delivery systems.