Parallel cortical-brainstem pathways to attentional analgesia

Pain demands attention, yet pain can be reduced by focusing attention elsewhere. The neural processes involved in this robust psychophysical phenomenon, attentional analgesia, are still being defined. Our previous fMRI study linked activity in the brainstem triad of locus coeruleus (LC), rostral ventromedial medulla (RVM) and periaqueductal grey (PAG) with attentional analgesia. Here we identify and model the functional interactions between these regions and the cortex in healthy human subjects (n = 57), who received painful thermal stimuli whilst simultaneously performing a visual attention task. RVM activity encoded pain intensity while contralateral LC activity correlated with attentional analgesia. Psycho-Physiological Interaction analysis and Dynamic Causal Modelling identified two parallel paths between forebrain and brainstem. These connections are modulated by attentional demand: a bidirectional anterior cingulate cortex (ACC) – right-LC loop, and a top-down influence of task on ACC-PAG-RVM. By recruiting discrete brainstem circuits, the ACC is able to modulate nociceptive input to reduce pain in situations of conflicting attentional demand

Identification of a Rare Coding Variant in Complement 3 Associated with Age-related Macular Degeneration

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry matched controls revealed two large-effect rare variants; previously described R1210C in the CFH gene (fcase = 0.51%, fcontrol = 0.02%, OR = 23.11), and newly identified K155Q in the C3 gene (fcase = 1.06%, fcontrol = 0.39%, OR = 2.68). The variants suggest decreased inhibition of C3 by Factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology

A frontal attention mechanism in the visual mismatch negativity

Automatic detection of environmental change is a core component of attention. The mismatch negativity (MMN), an electrophysiological marker of this mechanism, has been studied prominently in the auditory domain, with cortical generators identified in temporal and frontal regions. Here, we combined electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to assess whether the underlying frontal regions associated with auditory change detection also play a role in visual change detection. Twenty healthy young adults completed a visual MMN task in separate EEG and fMRI sessions. Region of interest analyses were conducted on left and right middle frontal (MFG) and inferior frontal (IFG) gyri, i.e., the frontal areas identified as potential auditory MMN generators. A significant increase in activation was observed in the left IFG and MFG in response to blocks containing deviant stimuli. These findings suggest that a frontal mechanism is involved in the detection of change in the visual MMN. Our results support the notion that frontal mechanisms underlie attention switching, as measured via MMN, across multiple modalities

Physiological Noise Modeling and Analysis for Spinal Cord fMRI

Spinal cord functional imaging offers new insights into normal sensorimotor processing and monitoring disease processes affecting the cord. However, all imaging-based techniques suffer from unwanted contributions to the measured signal from nonneuronal physiological sources. Broadly, these noise sources can be grouped into those arising from cardiac or respiratory processes, as well as from their interaction. Different techniques for estimating and removing physiological noise, their implication for functional magnetic resonance imaging (fMRI) analysis, and their implementation within the framework of the general linear model will be demonstrated. Recommendations for preprocessing spinal fMRI data will be given, such as how to avoid potential inflation of recorded T-statistics and whether prewhitening is appropriate for processing spinal fMRI data. Finally, techniques for the registration of spinal cord functional imaging data to a standard spinal cord, for the purpose of group analysis, will be presented along with techniques for estimating significance from group data

Spinal Cord fMRI

Blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI) is widely used by the neuroimaging community for studies of the brain, but remains controversial in the spinal cord despite demonstrations of technical feasibility. As yet the majority of motor studies have focussed on hand movement or finger tapping, while painful and non painful thermal, brushing and electrical stimuli have been used in sensory studies. These studies face challenges relating to the location and anatomy of the spinal cord, magnetic field inhomogeneities, motion, reduced receiver coil sensitivity relative to the brain, and even a lack of tailored tools for the post-processing chain. Overcoming these obstacles have been a major topic for activity in the field, with advanced shimming techniques, refined sequences, enhanced coil designs and tools for co-registration and physiological noise reduction emerging to address various issues. Those looking to undertake spinal fMRI should perform a careful preliminary investigation in order to appropriately design their study for robust results, some guidance on which is provided in this chapter

Magnetic resonance imaging-based compartmentation and its application to measuring metabolite concentrations in the frontal lobe

Partial volume mixing of water compartments within a spectros-copy voxel (e.g. cerebrospinal fluid within a 'brain' voxel) may, if not corrected for, lead to underestimation of brain metabolite concentrations. To correct for this source of bias, a new imaging-based method of compartmentation analysis is presented. Brain water, cerebrospinal fluid and solid matter content were obtained from proton density- and T2-weighted images of the brain and an external standard in 10 healthy young males (21 to 30 years), and results compared with a previously-described technique based on spectroscopy. Mean (SD) fractional water content (β(MR)) of the 2 x 2 x 2 cm3 voxel in the frontal lobes was 0.79 (0.03) by imaging, slightly but significantly (p = 0.03) smaller than the value of 0.83 (0.03) obtained by spectroscopy. From water-suppressed spectra recorded at five echo times, using β(MR) determined by imaging, the T2-corrected concentrations of compounds containing N- acetylaspartate, creatine, choline and myo-inositol were 10.6 (1.0), 8.0 (0.9), 1.6 (0.3) and 3.7 (0.7) mmol.l-1 of brain, respectively. Imaging- based compartmentation is a rapid and straightforward technique, and can be performed on standard MR systems

A proton magnetic resonance spectroscopy study of age-related changes in frontal lobe metabolite concentrations

Ageing is associated with reduction of grey matter volume and it is reported that the frontal lobes are preferentially affected. We have applied quantitative magnetic resonance spectroscopy (MRS), incorporating measurement of brain tissue water content and metabolite T2 relaxation times, to determine absolute concentrations of the putative neuronal marker N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) compounds in the frontal lobe of 50 male subjects aged between 20 and 70 years (10 per decade). The fractional brain water content (βMR) did not change significantly as a function of age (r = 0.07, P = 0.65) and had a mean value of 81% (CV = 2%). The concentration (in millimoles per litre brain tissue) of NAA decreased significantly with age (r = -0.42, P = 0.003), with an overall decrease of 12% between the third and seventh decades. The concentrations of Cr and Cho did not change significantly with age. The interpretation of the age-dependent decrease in NAA concentration as reflecting either a reduction in neuronal volume, number or function is discussed

Reliability of resting-state functional connectivity in the human spinal cord: assessing the impact of distinct noise sources

The investigation of spontaneous fluctuations of the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord, where it has also generated initial interest from a clinical perspective. A number of resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated robust functional connectivity between the time-series of BOLD fluctuations in bilateral dorsal horns and between those in bilateral ventral horns, in line with the functional neuroanatomy of the spinal cord. A necessary step prior to extension to clinical studies is assessing the reliability of such resting-state signals, which we aimed to do here in a group of 45 healthy young adults at the clinically prevalent field-strength of 3T. When investigating connectivity in the entire cervical spinal cord, we observed fair to good reliability for dorsal-dorsal and ventral-ventral connectivity, whereas reliability was poor for within- and between-hemicord dorsal-ventral connectivity. Considering how prone spinal cord fMRI is to noise, we extensively investigated the impact of distinct noise sources and made two crucial observations: removal of physiological noise led to a reduction in functional connectivity strength and reliability – due to the removal of stable and participant-specific noise patterns – whereas removal of thermal noise considerably increased the detectability of functional connectivity without a clear influence on reliability. Finally, we also assessed connectivity within spinal cord segments and observed that while the pattern of connectivity was similar to that of whole cervical cord, reliability at the level of single segments was consistently poor. Taken together, our results demonstrate the presence of reliable resting-state functional connectivity in the human spinal cord even after thoroughly accounting for physiological and thermal noise, but at the same time urge caution if focal changes in connectivity (e.g. due to segmental lesions) are to be studied, especially in a longitudinal manner