Forging a path to mesoscopic imaging success with ultra-high field functional magnetic resonance imaging

Functional magnetic resonance imaging (fMRI) studies with ultra-high field (UHF, 7+ Tesla) technology enable the acquisition of high-resolution images. In this work, we discuss recent achievements in UHF fMRI at the mesoscopic scale, on the order of cortical columns and layers, and examine approaches to addressing common challenges. As researchers push to smaller and smaller voxel sizes, acquisition and analysis decisions have greater potential to degrade spatial accuracy, and UHF fMRI data must be carefully interpreted. We consider the impact of acquisition decisions on the spatial specificity of the MR signal with a representative dataset with 0.8 mm isotropic resolution. We illustrate the trade-offs in contrast with noise ratio and spatial specificity of different acquisition techniques and show that acquisition blurring can increase the effective voxel size by as much as 50% in some dimensions. We further describe how different sources of degradations to spatial resolution in functional data may be characterized. Finally, we emphasize that progress in UHF fMRI depends not only on scientific discovery and technical advancement, but also on informal discussions and documentation of challenges researchers face and overcome in pursuit of their goals.This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.     

Reward‐related ventral striatum reactivity mediates gender‐specific effects of a galanin remote enhancer haplotype on problem drinking

The neuropeptide galanin has been implicated in the regulation of appetitive and consummatory behaviors. Prior studies have shown that direct injection of galanin into the hypothalamus results in increased release of dopamine (DA) in the nucleus accumbens (NAcc), and parallel increases in food and alcohol consumption. These studies are consistent with a role of hypothalamic galanin in regulating reward system reactivity. In humans, a common functional haplotype (GAL5.1) within a remote enhancer region upstream of the galanin gene (GAL) affects promoter activity and galanin expression in hypothalamic neurons in vitro. Given the effects of hypothalamic galanin on NAcc DA release and the effects of the GAL5.1 haplotype on GAL expression, we examined the impact of this functional genetic variation on human reward‐related ventral striatum (VS) reactivity. Using an imaging genetics strategy in Caucasian individuals (N = 138, 72 women) participating in the ongoing Duke Neurogenetics Study, we report a significant gender‐by‐genotype interaction (right hemisphere: F_1,134 = 8.08, P = 0.005; left hemisphere: F_1,134 = 5.39, P = 0.022), such that homozygosity for the GG haplotype, which predicts greater GAL expression, is associated with relatively increased VS reactivity in women (n = 50, right hemisphere: P = 0.015; left hemisphere: P = 0.060), but not in men (N = 49, P‐values > 0.10). Furthermore, these differences in VS reactivity correlated positively with differences in alcohol use, such that VS reactivity mediated a gender‐specific association between GAL5.1 haplotype and problem drinking. Our current results support those in animal models implicating galanin signaling in neural pathways associated with appetitive and consummatory behaviors of relevance for understanding risk for substance use and abuse.     

A preliminary study suggests that nicotine and prefrontal dopamine affect cortico‐striatal areas in smokers with performance feedback

Nicotine and tonic dopamine (DA) levels [as inferred by catechol‐O‐methyl tranferase (COMT) Val158Met genotype] interact to affect prefrontal processing. Prefrontal cortical areas are involved in response to performance feedback, which is impaired in smokers. We investigated whether there is a nicotine × COMT genotype interaction in brain circuitry during performance feedback of a reward task. We scanned 23 healthy smokers (10 Val/Val homozygotes, 13 Met allele carriers) during two fMRI sessions while subjects were wearing a nicotine or placebo patch. A significant nicotine × COMT genotype interaction for BOLD signal during performance feedback in cortico‐striatal areas was seen. Activation in these areas during the nicotine patch condition was greater in Val/Val homozygotes and reduced in Met allele carriers. During negative performance feedback, the change in activation in error detection areas such as anterior cingulate cortex (ACC)/superior frontal gyrus on nicotine compared to placebo was greater in Val/Val homozygotes compared to Met allele carriers. With transdermal nicotine administration, Val/Val homozygotes showed greater activation with performance feedback in the dorsal striatum, area associated with habitual responding. In response to negative feedback, Val/Val homozygotes had greater activation in error detection areas, including the ACC, suggesting increased sensitivity to loss with nicotine exposure. Although these results are preliminary due to small sample size, they suggest a possible neurobiological mechanism underlying the clinical observation that Val/Val homozygotes, presumably with elevated COMT activity compared to Met allele carriers and therefore reduced prefrontal DA levels, have poorer outcomes with nicotine replacement therapy .     

Increased functional connectivity with puberty in the mentalising network involved in social emotion processing

This article is part of a Special Issue “Puberty and Adolescence”.     

The role of brain‐derived neurotrophic factor in learned fear processing: an awake rat fMRI study

Brain‐derived neurotrophic factor (BDNF) signaling is implicated in the etiology of many psychiatric disorders associated with altered emotional processing. Altered peripheral (plasma) BDNF levels have been proposed as a biomarker for neuropsychiatric disease risk in humans. However, the relationship between peripheral and central BDNF levels and emotional brain activation is unknown. We used heterozygous BDNF knockdown rats (BDNF^+/?) to examine the effects of genetic variation in the BDNF gene on peripheral and central BDNF levels and emotional brain activation as assessed by awake functional magnetic resonance imaging (fMRI). BDNF^+/? and control rats were trained to associate a flashing light (conditioned stimulus; CS) with foot‐shock, and brain activation in response to the CS was measured 24 h later in awake rats using fMRI. Central and peripheral BDNF levels were decreased in BDNF^+/? rats compared with control rats. Activation of fear circuitry (amygdala, periaqueductal gray, granular insular) was seen in control animals; however, activation of this circuitry was absent in BDNF^+/? animals. Behavioral experiments confirmed impaired conditioned fear responses in BDNF^+/? rats, despite intact innate fear responses. These data confirm a positive correlation [r = 0.86, 95% confidence interval (0.55, 0.96); P = 0.0004] between peripheral and central BDNF levels and indicate a functional relationship between BDNF levels and emotional brain activation as assessed by fMRI. The results demonstrate the use of rodent fMRI as a sensitive tool for measuring brain function in preclinical translational studies using genetically modified rats and support the use of peripheral BDNF as a biomarker of central affective processing.