Effective Connectivity Measured Using Optogenetically Evoked Hemodynamic Signals Exhibits Topography Distinct from Resting State Functional Connectivity in the Mouse.

Brain connectomics has expanded from histological assessment of axonal projection connectivity (APC) to encompass resting state functional connectivity (RS-FC). RS-FC analyses are efficient for whole-brain mapping, but attempts to explain aspects of RS-FC (e.g., interhemispheric RS-FC) based on APC have been only partially successful. Neuroimaging with hemoglobin alone lacks specificity for determining how activity in a population of cells contributes to RS-FC. Wide-field mapping of optogenetically defined connectivity could provide insights into the brain's structure-function relationship. We combined optogenetics with optical intrinsic signal imaging to create an efficient, optogenetic effective connectivity (Opto-EC) mapping assay. We examined EC patterns of excitatory neurons in awake, Thy1-ChR2 transgenic mice. These Thy1-based EC (Thy1-EC) patterns were evaluated against RS-FC over the cortex. Compared to RS-FC, Thy1-EC exhibited increased spatial specificity, reduced interhemispheric connectivity in regions with strong RS-FC, and appreciable connection strength asymmetry. Comparing the topography of Thy1-EC and RS-FC patterns to maps of APC revealed that Thy1-EC more closely resembled APC than did RS-FC. The more general method of Opto-EC mapping with hemoglobin can be determined for 100 sites in single animals in under an hour, and is amenable to other neuroimaging modalities. Opto-EC mapping represents a powerful strategy for examining evolving connectivity-related circuit plasticity.

Magnetic resonance imaging-directed transperineal limited-mapping prostatic biopsies to diagnose prostate cancer: a Scottish experience.

BACKGROUND: Transperineal prostatic biopsy is firmly established as an important tool in the diagnosis of prostate cancer. The benefit of additional imaging (magnetic resonance imaging) to target biopsy remains to be fully addressed. METHODS: Using a cohort of consecutive patients undergoing transperineal template mapping biopsies, we studied positive biopsies in the context of magnetic resonance imaging findings and examined the accuracy of magnetic resonance imaging in predicting the location of transperineal template mapping biopsies-detected prostate cancer. RESULTS: Forty-four patients (mean age: 65 years, range 53-78) underwent transperineal template mapping biopsies. Thirty-four patients had 1-2 and 10 patients had ≥3 previous transrectal ultrasound scan-guided biopsies. The mean prostate-specific antigen was 15 ng/mL (range 2.5-79 ng/mL). High-grade prostatic intraepithelial neoplasia was found in 12 (27%) patients and prostate cancer with Gleason <7, 7 and >7 in 13, 10 and 8 patients, respectively. Suspicious lesions on magnetic resonance imaging scans were scored from 1 to 5. In 28 patients, magnetic resonance imaging detected lesions with score ≥3. Magnetic resonance imaging correctly localised transperineal template mapping biopsies-detected prostate cancer in a hemi-gland approach, particularly in a right to left manner (79% positive prediction rate), but not in a quadrant approach (33% positive prediction rate). CONCLUSION: Our findings support the notion of magnetic resonance imaging-based selection of patients for transperineal template mapping biopsies and that lesions revealed by magnetic resonance imaging are likely useful for targeted biopsies.

Early measurement of pulsatility and resistive indexes: correlation with long-term renal transplant function.

PURPOSE: To correlate pulsatility index (PI) and resistive index (RI) measured at early specific intervals after transplantation with 1-year estimated glomerular filtration rate (eGFR) and death-censored transplant survival to assess the long-term prognostic value of these Doppler indexes. MATERIALS AND METHODS: The local ethics committee was consulted, and no formal approval was required. This retrospective review included 178 consecutive patients (111 male, 67 female; mean age, 43.9 years ± 13.4 [standard deviation]; age range, 16-72 years) undergoing first deceased-donor renal transplantation between 1997 and 2000. All patients were identified from a prospectively maintained database. Spectral Doppler analysis was performed within 1 week after transplantation in all patients and between 1 week and 3 months after transplantation in 124 patients. Average PI and RI were determined from measurements obtained in the upper, lower, and interpolar regions. For statistical analysis, the χ(2) test, analysis of variance, the Student t test, Kaplan-Meier survival plots, and Cox proportional hazards models were used. RESULTS: Within 1 week after transplantation, there was a significant association between PI and 1-year eGFR when analyzed as tertiles (P = .02). Between 1 week and 3 months after transplantation, there was a significant relationship between 1-year eGFR and both PI and RI when comparing the lowest and highest tertiles (47.5 mL/min/1.73 m(2) for PI <1.26 vs 32.7 mL/min/1.73 m(2) for PI >1.49 [P = .01], 42.8 mL/min/1.73 m(2) for RI <0.69 vs 32.3 mL/min/1.73 m(2) for RI >0.74 [P = .03]). Both PI and RI were independent predictors of death-censored transplant survival (hazard ratio, 1.68 per unit [P < .001] and 260.4 per unit, respectively [P = .02]). CONCLUSION: PI and RI in the early posttransplantation period correlate with long-term transplant function and can potentially be used as prognostic markers to aid risk stratification for future transplant dysfunction.

Altered hemodynamics contribute to local but not remote functional connectivity disruption due to glioma growth.

Glioma growth can cause pervasive changes in the functional connectivity (FC) of brain networks, which has been associated with re-organization of brain functions and development of functional deficits in patients. Mechanisms underlying functional re-organization in brain networks are not understood and efforts to utilize functional imaging for surgical planning, or as a biomarker of functional outcomes are confounded by the heterogeneity in available human data. Here we apply multiple imaging modalities in a well-controlled murine model of glioma with extensive validation using human data to explore mechanisms of FC disruption due to glioma growth. We find gliomas cause both local and distal changes in FC. FC changes in networks proximal to the tumor occur secondary to hemodynamic alterations but surprisingly, remote FC changes are independent of hemodynamic mechanisms. Our data strongly implicate hemodynamic alterations as the main driver of local changes in measurements of FC in patients with glioma.

Separability of calcium slow waves and functional connectivity during wake, sleep, and anesthesia.

Modulation of brain state, e.g., by anesthesia, alters the correlation structure of spontaneous activity, especially in the delta band. This effect has largely been attributed to the ∼ 1 Hz slow oscillation that is characteristic of anesthesia and nonrapid eye movement (NREM) sleep. However, the effect of the slow oscillation on correlation structures and the spectral content of spontaneous activity across brain states (including NREM) has not been comprehensively examined. Further, discrepancies between activity dynamics observed with hemoglobin versus calcium (GCaMP6) imaging have not been reconciled. Lastly, whether the slow oscillation replaces functional connectivity (FC) patterns typical of the alert state, or superimposes on them, remains unclear. Here, we use wide-field calcium imaging to study spontaneous cortical activity in awake, anesthetized, and naturally sleeping mice. We find modest brain state-dependent changes in infraslow correlations but larger changes in GCaMP6 delta correlations. Principal component analysis of GCaMP6 sleep/anesthesia data in the delta band revealed that the slow oscillation is largely confined to the first three components. Removal of these components revealed a correlation structure strikingly similar to that observed during wake. These results indicate that, during NREM sleep/anesthesia, the slow oscillation superimposes onto a canonical FC architecture.

Long-term outcome of transplant renal artery stenosis managed conservatively or by radiological intervention.

The natural history and optimal treatment of transplant renal artery stenosis (TRAS) is poorly defined. Few studies reported long-term clinical outcomes. A single centre analysis of 43 patients diagnosed with TRAS 1990-2003 was performed. Twenty-seven had percutaneous intervention (including 10 patients who had >1 intervention) and 16 were managed conservatively at the discretion of the attending clinicians. Transplant function was assessed by slope of estimated glomerular filtration rate (eGFR) over five yr of follow-up. Patients in the intervention group had lower mean eGFR (36.3 mL/min/1.73 m(2) vs. 46.3 mL/min/1.73 m(2); p = 0.07) at baseline. Five transplants in the intervention group failed (including two as a direct result of intervention) and one in the conservative group failed. There was no significant difference in the rate of deterioration in renal function (mean slope of eGFR minus 0.8 mL/min/yr and minus 1.0 mL/min/yr in the intervention and conservative groups, respectively; p = 0.79). There was no significant difference in blood pressure or number of anti-hypertensive agents between the groups at any time point. Baseline Doppler ultrasound indices showed no significant correlation with slope of eGFR in either group. Our data demonstrate that selected patients with TRAS can be managed without intervention and that this approach is associated with good long-term outcome. Selection of appropriate patients for intervention remains difficult and larger randomized studies are required.

Functional connectivity structure of cortical calcium dynamics in anesthetized and awake mice.

The interplay between hemodynamic-based markers of cortical activity (e.g. fMRI and optical intrinsic signal imaging), which are an indirect and relatively slow report of neural activity, and underlying synaptic electrical and metabolic activity through neurovascular coupling is a topic of ongoing research and debate. As application of resting state functional connectivity measures is extended further into topics such as brain development, aging and disease, the importance of understanding the fundamental physiological basis for functional connectivity will grow. Here we extend functional connectivity analysis from hemodynamic- to calcium-based imaging. Transgenic mice (n = 7) expressing a fluorescent calcium indicator (GCaMP6) driven by the Thy1 promoter in glutamatergic neurons were imaged transcranially in both anesthetized (using ketamine/xylazine) and awake states. Sequential LED illumination (λ = 454, 523, 595, 640nm) enabled concurrent imaging of both GCaMP6 fluorescence emission (corrected for hemoglobin absorption) and hemodynamics. Functional connectivity network maps were constructed for infraslow (0.009-0.08Hz), intermediate (0.08-0.4Hz), and high (0.4-4.0Hz) frequency bands. At infraslow and intermediate frequencies, commonly used in BOLD fMRI and fcOIS studies of functional connectivity and implicated in neurovascular coupling mechanisms, GCaMP6 and HbO2 functional connectivity structures were in high agreement, both qualitatively and also quantitatively through a measure of spatial similarity. The spontaneous dynamics of both contrasts had the highest correlation when the GCaMP6 signal was delayed with a ~0.6-1.5s temporal offset. Within the higher-frequency delta band, sensitive to slow wave sleep oscillations in non-REM sleep and anesthesia, we evaluate the speed with which the connectivity analysis stabilized and found that the functional connectivity maps captured putative network structure within time window lengths as short as 30 seconds. Homotopic GCaMP6 functional connectivity maps at 0.4-4.0Hz in the anesthetized states show a striking correlated and anti-correlated structure along the anterior to posterior axis. This structure is potentially explained in part by observed propagation of delta-band activity from frontal somatomotor regions to visuoparietal areas. During awake imaging, this spatio-temporal quality is altered, and a more complex and detailed functional connectivity structure is observed. The combined calcium/hemoglobin imaging technique described here will enable the dissociation of changes in ionic and hemodynamic functional structure and neurovascular coupling and provide a framework for subsequent studies of neurological disease such as stroke.

Imaging in renal transplantation.

Renal transplantation is the best treatment option for chronic renal failure, with marked improvement in social activity, work, and family life. In addition to these obvious improvements, it is an extremely cost-effective procedure when successful. Ultrasonography plays a major role in the imaging of these patients, and ultrasound (including color Doppler) is helpful to the transplant physician in detecting graft dysfunction and peritransplant collections, some of which may be drained under ultrasound guidance. It is also helpful in the diagnosis of chronic vascular complications including transplant artery stenosis and arteriovenous fistula. It has no specific application in the diagnosis of chronic rejection.