Reproducibility of a ramping protocol to measure cerebral vascular reactivity using functional magnetic resonance imaging

Though individual differences in arterial carbon dioxide and oxygen levels inherently exist, the degree of their influence on cerebral vascular reactivity (CVR) is less clear. We examined the reproducibility of BOLD signal changes to an iso‐oxic ramping P_etCO₂ protocol. CVR changes were induced by altering P_etCO₂ while holding P_etO₂ constant using a computer‐controlled sequential gas delivery (SGD) device. Two MRI scans, each including a linear change in P_etCO₂, were performed using a 3‐Tesla (3T) scanner. This ramp sequence consisted of 1 min at 30 mmHg followed by 4 min period during where P_etCO₂ was linearly increased from 30 to 50 mmHg, 1 min at 51 mmHg, and concluded with 4 min at baseline. The protocol was repeated at a separate visit with 3 days between visits (minimum). Intraclass correlation coefficients (ICC) and coefficients of variation (CV) were used to verify reproducibility. Eleven subjects (6 females; mean age 26.5 ± 5.7 years) completed the full testing protocol. Good reproducibility was observed for the within‐visit ramp sequence (Visit 1: ICC = 0.82, CV = 6.5%; Visit 2: ICC = 0.74, CV = 6.4%). Similarly, ramp sequence were reproducible between visits (Scan 1: ICC = 0.74, CV = 6.5%; Scan 2: ICC = 0.66, CV = 6.1%). Establishing reproducible methodologies for measuring BOLD signal changes in response to P_etCO₂ alterations using a ramp protocol will allow researchers to study CVR functionality. Finally, adding a ramping protocol to CVR studies could provide information about changes in CVR over a broad range of P_etCO₂.     

Parallel group ICA+ICA: Joint estimation of linked functional network variability and structural covariation with application to schizophrenia

There is growing evidence that rather than using a single brain imaging modality to study its association with physiological or symptomatic features, the field is paying more attention to fusion of multimodal information. However, most current multimodal fusion approaches that incorporate functional magnetic resonance imaging (fMRI) are restricted to second‐level 3D features, rather than the original 4D fMRI data. This trade‐off is that the valuable temporal information is not utilized during the fusion step. Here we are motivated to propose a novel approach called “parallel group ICA+ICA” that incorporates temporal fMRI information from group independent component analysis (GICA) into a parallel independent component analysis (ICA) framework, aiming to enable direct fusion of first‐level fMRI features with other modalities (e.g., structural MRI), which thus can detect linked functional network variability and structural covariations. Simulation results show that the proposed method yields accurate intermodality linkage detection regardless of whether it is strong or weak. When applied to real data, we identified one pair of significantly associated fMRI‐sMRI components that show group difference between schizophrenia and controls in both modalities, and this linkage can be replicated in an independent cohort. Finally, multiple cognitive domain scores can be predicted by the features identified in the linked component pair by our proposed method. We also show these multimodal brain features can predict multiple cognitive scores in an independent cohort. Overall, results demonstrate the ability of parallel GICA+ICA to estimate joint information from 4D and 3D data without discarding much of the available information up front, and the potential for using this approach to identify imaging biomarkers to study brain disorders.     

The spatial chronnectome reveals a dynamic interplay between functional segregation and integration

The brain is highly dynamic, reorganizing its activity at different interacting spatial and temporal scales, including variation within and between brain networks. The chronnectome is a model of the brain in which nodal activity and connectivity patterns change in fundamental and recurring ways over time. Most literature assumes fixed spatial nodes/networks, ignoring the possibility that spatial nodes/networks may vary in time. Here, we introduce an approach to calculate a spatially fluid chronnectome (called the spatial chronnectome for clarity), which focuses on the variations of networks coupling at the voxel level, and identify a novel set of spatially dynamic features. Results reveal transient spatially fluid interactions between intra‐ and internetwork relationships in which brain networks transiently merge and separate, emphasizing dynamic segregation and integration. Brain networks also exhibit distinct spatial patterns with unique temporal characteristics, potentially explaining a broad spectrum of inconsistencies in previous studies that assumed static networks. Moreover, we show anticorrelative connections to brain networks are transient as opposed to constant across the entire scan. Preliminary assessments using a multi‐site dataset reveal the ability of the approach to obtain new information and nuanced alterations that remain undetected during static analysis. Patients with schizophrenia (SZ) display transient decreases in voxel‐wise network coupling within visual and auditory networks, and higher intradomain coupling variability. In summary, the spatial chronnectome represents a new direction of research enabling the study of functional networks which are transient at the voxel level, and the identification of mechanisms for within‐ and between‐subject spatial variability.     

MRI assessment of cerebral oxygen metabolism in cocaine‐addicted individuals: hypoactivity and dose dependence

Long‐term cocaine use is known to negatively impact neural and cerebrovascular systems. However, the use of imaging markers to separately assess these parameters remains challenging. The primary reason is that most functional imaging markers, such as cerebral blood flow, functional connectivity, and task‐evoked functional MRI, are known to reflect a complex interplay between neural and vascular components, thus the interpretation of the results is not straightforward. The goal of the present study is to examine neural‐activity‐specific changes in cocaine addiction, using cerebral metabolic rate of oxygen (CMRO2) as a surrogate marker of aggregated neural activity. We applied a recently developed CMRO2 technique in 13 cocaine‐addicted subjects and 13 age‐ and gender‐matched control subjects, and examined the impact of long‐term cocaine use on CMRO2. Our results showed that CMRO2 in cocaine‐addicted subjects (152 ± 16 µmol/100 g/min) is significantly lower (p = 0.031) than that in controls (169 ± 20 µmol/100 g/min). Furthermore, the severity of this decreased metabolism is associated with lifetime cocaine use (p = 0.05). Additionally, the CMRO2 reduction was accompanied by a trend of decrease in cerebral blood flow (p = 0.058), but venous oxygenation was unaffected (p = 0.96), which suggested that the CMRO2 change may be attributed to a vascular deficiency in chronic cocaine users. To our knowledge, this is the first study to measure CMRO2 in cocaine‐addicted individuals. Our findings suggest that CMRO2 may be a promising approach for assessing the long‐term effects of cocaine use on the brain. Copyright © 2014 John Wiley & Sons, Ltd.     

The role of acetylcholine in cocaine addiction.

Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.     

Long-term renal function in kidneys from non-heart-beating donors: A single-center experience

BACKGROUND: Cadaveric kidneys from brain-stem-dead donors continue to be limited because the number of donors has reached a plateau. Wide recruitment of non-heart-beating donors (NHBD) could significantly increase the donor pool. NHBD renal transplants are underused because of the concern of poor quality graft function from such donors. In response to this perception, we reviewed 46 NHBD renal transplants performed in our center since 1998. METHODS: All NHBD kidneys were machine-perfused using the Newcastle continuous-hypothermic pulsatile preservation system before transplantation. A control heart-beating-donor (HBD) group was taken as the next consecutive HBD renal transplant to the NHBD transplant. The outcome and quality of function of the groups of renal transplants were analyzed for short-term and long-term performance. RESULTS: The renal transplant patients were matched for donor and recipient factors. Survival rates for allografts and patients were similar for 1 to 3 years. There was an increased incidence of delayed graft function in the NHBD renal transplants in the perioperative period. The creatinine clearance was 22.8+/-2.3 mL/minute for NHBD patients and 44.4+/-2.9 mL/minute for HBD patients at the time of discharge from hospital. This difference equalized after 3 months and the creatinine clearance for NHBD was 44.2+/-2.4 mL/minute and for HBD 49.2+/-3.4 mL/minute. CONCLUSIONS: Our results for NHBD renal transplants confirm that such grafts suffer primary warm ischemic injury, shown by the increased incidence of acute tubular necrosis and consequent delayed graft function. This produced poor renal function at the time of hospital discharge. After 3 months, the renal function of NHBD cases improved to the level seen in HBD patients.     

SSeCKS immunolabeling in rat primary sensory neurons

SSeCKS (src suppressed C kinase substrate) is a protein kinase C substrate that may play a role in tumor suppression. Recently described in fibroblasts, testes and mesangial cells, SSeCKS may have a function in the control of cell signaling and cytoskeletal arrangement. To investigate the distribution of SSeCKS throughout the nervous system, representative sections of brain, spinal cord and dorsal root ganglia were processed using immunofluorescence. Labeling of central axonal collaterals of primary sensory neurons was observed in the dorsal horn at all spinal levels. SSeCKS-immunoreactivity was also observed in the cerebellum, medulla and sensory ganglia (including trigeminal ganglia). The pattern and distribution of anti-SSeCKS labeling in dorsal root ganglia and the dorsal horn of the spinal cord was similar to that observed for other markers of small primary sensory neurons. Therefore, the coexistence of SSeCKS with substance P, CGRP and acid phosphatase was examined in sections of sensory ganglia, spinal cord and medulla using double immunofluorescent labeling for SSeCKS and substance P/CGRP or sequential SSeCKS immunofluorescence and acid phosphatase/fluoride-resistant acid phosphatase enzyme histochemistry. A small portion of the SSeCKS-labeled cell bodies appeared to represent a subpopulation of substance P (4.8%) and CGRP (4.7%) containing neurons, while 45.0% contained fluoride-resistant acid phosphatase reactivity. These results indicate that SSeCKS has a restricted distribution within the nervous system and that expression of this protein may reflect the specific signaling requirements of a distinct population of nociceptive sensory neurons.     

Preservation of a functionally intact neuronal network after global ischemia

Although conventional histological techniques demonstrated preservation by drug treatment of neuronal perikarya in the hippocampal CA1 region in animals subjected to short periods of transient ischemia, uncertainty exists regarding whether the anatomical connections with these neurons are intact and functional. The hippocampal theta rhythm is dependent upon intact connections to the CA1 pyramidal neurons and is a useful predictor of functional hippocampal integrity. Hippocampal theta was quantitated by power spectral analysis in rats subjected to 30 min of 4-vessel occlusion (4-VO) and treatment with the neuroprotective antioxidant, LY231617. The 4-VO destroyed CA1 neurons and reduced the amount of theta, however, LY231617 protected CA1 neurons histologically and totally preserved the hippocampal theta rhythm. We conclude that histological preservation is indicative of functional integrity.