Changes in Intratumor Blood Flow After Carbon-Ion Radiation Therapy for Early-Stage Breast Cancer.

Purpose: This study aimed to quantify the changes in intratumoral blood flow after carbon-ion radiation therapy (CIRT) for early-stage breast cancer and analyze their clinical significance. Patients and Methods: We included 38 patients with early-stage breast cancer who underwent CIRT. Dynamic imaging was performed using a 3T superconducting magnetic resonance scanner to quantify the washin index (idx), which reflects contrast uptake, and washout idx, which reflects the rate of contrast washout from tumor tissue. The changes in the apparent diffusion coefficient, washin idx, and washout idx were examined before CIRT and at 1 and 3 months after treatment. Clinical factors and imaging features were examined using univariate and receiver operating characteristic curve analyses to identify factors predicting clinical complete response (cCR). Results: The median observation period after CIRT was 51 (range: 12-122) months. During the observation period, 31 of the 38 patients achieved cCR, and 22 achieved cCR within 12 months. Tumor size (P < .001), washin idx (P = .043), and washout idx (P < .001) decreased significantly 1-month after CIRT. In contrast, the apparent diffusion coefficient values (P < .001) increased significantly 1-month after CIRT. Univariate analysis suggested that the washin idx after 1 and 3 months of CIRT was associated with cCR by 12 months post-CIRT (P = .028 and .021, respectively). No other parameters were associated with cCR by 12 months post-CIRT. Furthermore, receiver operating characteristic curve analyses showed that the area under the curve values of washin idx after 1 and 3 months of CIRT was 0.78 (specificity 75%, sensitivity 80%) and 0.73 (specificity 75%, sensitivity 71%), respectively. Conclusion: Tumor changes can be quantified early after CIRT using contrast-enhanced magnetic resonance imaging in patients with breast cancer. Washin idx values 1 and 3 months after CIRT were associated with cCR within 12 months post-CIRT.

Plastic vasomotion entrainment.

The presence of global synchronization of vasomotion induced by oscillating visual stimuli was identified in the mouse brain. Endogenous autofluorescence was used and the vessel 'shadow' was quantified to evaluate the magnitude of the frequency-locked vasomotion. This method allows vasomotion to be easily quantified in non-transgenic wild-type mice using either the wide-field macro-zoom microscopy or the deep-brain fiber photometry methods. Vertical stripes horizontally oscillating at a low temporal frequency (0.25 Hz) were presented to the awake mouse, and oscillatory vasomotion locked to the temporal frequency of the visual stimulation was induced not only in the primary visual cortex but across a wide surface area of the cortex and the cerebellum. The visually induced vasomotion adapted to a wide range of stimulation parameters. Repeated trials of the visual stimulus presentations resulted in the plastic entrainment of vasomotion. Horizontally oscillating visual stimulus is known to induce horizontal optokinetic response (HOKR). The amplitude of the eye movement is known to increase with repeated training sessions, and the flocculus region of the cerebellum is known to be essential for this learning to occur. Here, we show a strong correlation between the average HOKR performance gain and the vasomotion entrainment magnitude in the cerebellar flocculus. Therefore, the plasticity of vasomotion and neuronal circuits appeared to occur in parallel. Efficient energy delivery by the entrained vasomotion may contribute to meeting the energy demand for increased coordinated neuronal activity and the subsequent neuronal circuit reorganization.

Astrocyte switch to the hyperactive mode.

Increasing pieces of evidence have suggested that astrocyte function has a strong influence on neuronal activity and plasticity, both in physiological and pathophysiological situations. In epilepsy, astrocytes have been shown to respond to epileptic neuronal seizures; however, whether they can act as a trigger for seizures has not been determined. Here, using the copper implantation method, spontaneous neuronal hyperactivity episodes were reliably induced during the week following implantation. With near 24-h continuous recording for over 1 week of the local field potential with in vivo electrophysiology and astrocyte cytosolic Ca2+ with the fiber photometry method, spontaneous occurrences of seizure episodes were captured. Approximately 1 day after the implantation, isolated aberrant astrocyte Ca2+ events were often observed before they were accompanied by neuronal hyperactivity, suggesting the role of astrocytes in epileptogenesis. Within a single developed episode, astrocyte Ca2+ increase preceded the neuronal hyperactivity by ~20 s, suggesting that actions originating from astrocytes could be the trigger for the occurrence of epileptic seizures. Astrocyte-specific stimulation by channelrhodopsin-2 or deep-brain direct current stimulation was capable of inducing neuronal hyperactivity. Injection of an astrocyte-specific metabolic inhibitor, fluorocitrate, was able to significantly reduce the magnitude of spontaneously occurring neuronal hyperactivity. These results suggest that astrocytes have a role in triggering individual seizures and the reciprocal astrocyte-neuron interactions likely amplify and exacerbate seizures. Therefore, future epilepsy treatment could be targeted at astrocytes to achieve epilepsy control.

Anxiety control by astrocytes in the lateral habenula.

The potential role of astrocytes in lateral habenula (LHb) in modulating anxiety was explored in this study. The habenula are a pair of small nuclei located above the thalamus, known for their involvement in punishment avoidance and anxiety. Herein, we observed an increase in theta-band oscillations of local field potentials (LFPs) in the LHb when mice were exposed to anxiety-inducing environments. Electrical stimulation of LHb at theta-band frequency promoted anxiety-like behavior. Calcium (Ca2+) levels and pH in the cytosol of astrocytes and local brain blood volume changes were studied in mice expressing either a Ca2+ or a pH sensor protein specifically in astrocytes and mScarlet fluorescent protein in the blood plasma using fiber photometry. An acidification response to anxiety was observed. Photoactivation of archaerhopsin-T (ArchT), an optogenetic tool that acts as an outward proton pump, results in intracellular alkalinization. Photostimulation of LHb in astrocyte-specific ArchT-expressing mice resulted in dissipation of theta-band LFP oscillation in an anxiogenic environment and suppression of anxiety-like behavior. These findings provide evidence that LHb astrocytes modulate anxiety and may offer a new target for treatment of anxiety disorders.