Papers by Daniel McFarlin
Two groups of participants were studied. Snake phobics consisted of 18 participants (n= 18, 15 fe... more Two groups of participants were studied. Snake phobics consisted of 18 participants (n= 18, 15 females, mean age 20.1, range 18-26) and Nonphobics consisted of 18 participants (n= 18, 7 females, mean age 29.6, range 29-58). Participants were right-handed and neurologically normal. Phobics met criteria for DSM-I V diagnosis of specific phobia of snakes and were absent of all clinical disorders as assessed by the Structured Clinical I nterview for the DSM-I V (First et al. 1996). Nonphobics were absent of all clinical disorders including specific phobia of snakes as assessed by the SCI D. I nformed consent in accordance with rules set by the University of Wisconsin at Madison Human Studies Committee was obtained from all participants prior to the experiment.
Birn, R. M.*, Shackman, A. J.*, Oler, J. A., Williams, L. E., McFarlin, D. R., Rogers, G. M., She... more Birn, R. M.*, Shackman, A. J.*, Oler, J. A., Williams, L. E., McFarlin, D. R., Rogers, G. M., Shelton, S. M., Alexander, A. L., Pine, D. S., Slattery, M. J., Davidson, R. J., Fox, A. S. & Kalin, N. H. (2014). Extreme early-life anxiety is associated with an evolutionarily conserved reduction in the strength of intrinsic functional connectivity between the dorsolateral prefrontal cortex and the central nucleus of the amygdala. Molecular Psychiatry, 19, 853.
Brain Connectivity, 2013
Granger causality analysis of functional magnetic resonance imaging (fMRI) blood-oxygen-level-dep... more Granger causality analysis of functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent signal data allows one to infer the direction and magnitude of influence that brain regions exert on one another. We employed a method for upsampling the time resolution of fMRI data that does not require additional interpolation beyond the interpolation that is regularly used for slice-timing correction. The mathematics for this new method are provided, and simulations demonstrate its viability. Using fMRI, 17 snake phobics and 19 healthy controls viewed snake, disgust, and neutral fish video clips preceded by anticipatory cues. Multivariate Granger causality models at the native 2-sec resolution and at the upsampled 400-ms resolution assessed directional associations of fMRI data among 13 anatomical regions of interest identified in prior research on anxiety and emotion. Superior sensitivity was observed for the 400-ms model, both for connectivity within each group and for group differences in connectivity. Context-dependent analyses for the 400-ms multivariate Granger causality model revealed the specific trial types showing group differences in connectivity. This is the first demonstration of effective connectivity of fMRI data using a method for achieving 400-ms resolution without sacrificing accuracy available at 2-sec resolution.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 15, 2014
Children with anxiety disorders (ADs) experience persistent fear and worries that are highly debi... more Children with anxiety disorders (ADs) experience persistent fear and worries that are highly debilitating, conferring risk for lifelong psychopathology. Anticipatory anxiety is a core clinical feature of childhood ADs, often leading to avoidance of uncertain and novel situations. Extensive studies in non-human animals implicate amygdala dysfunction as a critical substrate for early life anxiety. To test specific amygdala-focused hypotheses in preadolescent children with ADs, we used fMRI to characterize amygdala activation during uncertain anticipation and in response to unexpected stimuli. Forty preadolescent (age 8-12 years) children, 20 unmedicated AD patients and 20 matched controls completed an anticipation task during an fMRI scan. In the task, symbolic cues preceded fear or neutral faces, such that 'certain' cues always predicted the presentation of fear or neutral faces, whereas 'uncertain' cues were equally likely to be followed by fear or neutral faces. Bot...
NeuroImage, 2013
Experientially opening oneself to pain rather than avoiding it is said to reduce the mind's tende... more Experientially opening oneself to pain rather than avoiding it is said to reduce the mind's tendency toward avoidance or anxiety which can further exacerbate the experience of pain. This is a central feature of mindfulness-based therapies. Little is known about the neural mechanisms of mindfulness on pain. During a meditation practice similar to mindfulness, functional magnetic resonance imaging was used in expert meditators (>10,000 h of practice) to dissociate neural activation patterns associated with pain, its anticipation, and habituation. Compared to novices, expert meditators reported equal pain intensity, but less unpleasantness. This difference was associated with enhanced activity in the dorsal anterior insula (aI), and the anterior mid-cingulate (aMCC) the so-called 'salience network', for experts during pain. This enhanced activity during pain was associated with reduced baseline activity before pain in these regions and the amygdala for experts only. The reduced baseline activation in left aI correlated with lifetime meditation experience. This pattern of low baseline activity coupled with high response in aIns and aMCC was associated with enhanced neural habituation in amygdala and pain-related regions before painful stimulation and in the pain-related regions during painful stimulation. These findings suggest that cultivating experiential openness down-regulates anticipatory representation of aversive events, and increases the recruitment of attentional resources during pain, which is associated with faster neural habituation.
Gene, 1995
Mammalian pre-pro-vasoactive intestinal peptide (pre-proVIP) gives rise to the neuropeptides vaso... more Mammalian pre-pro-vasoactive intestinal peptide (pre-proVIP) gives rise to the neuropeptides vasoactive intestinal peptide (VIP) and peptide histidine isoleucine amide (PHI). The cDNA encoding chicken VIP was cloned and sequenced. The region of chicken pre-proVIP homologous to the mammalian PHI region is not followed by an amidation signal. This unusual feature suggests that processing of the precursor may be different in the chicken.
Developmental Dynamics, 1994
The enteric nervous system is largely formed from the vagal neural crest which arises from the ne... more The enteric nervous system is largely formed from the vagal neural crest which arises from the neuroaxis between somites 1-7. In order to evaluate the contribution of different regions of the vagal crest to the enteric nervous system, we marked crest cells by injecting somites 1-10 with a replication-defective spleen necrosis virus vector which contains the marker gene ZucZ. After incubation in X-gal, ZucZ-positive blue cells were found in the wall of the gut in three locations. Most were found at the peripheral edge of the developing circular muscle and within the developing submucosa, sites characteristic of developing ganglia. LacZ-positive cells in these ganglionic sites were always surrounded by HNK-1 immunostained cells, confirming their neural crest origin. LucZ-positive cells were also seen in a third location, the circular muscle layer of the esophagus and crop, and were separated from the HNK-1 positive ganglionic elements. These cells in the circular muscle are probably muscle cells derived from labeled mesodermal cells of the somite. Injection of somites 3, 4, 5, and 6 resulted in the largest percentage of preparations with ZucZ-positive crest-derived cells and in the largest number of positive cells in the gut. After injection of these somites, ZacZpositive crest-derived cells were found in all regions of the gut from the proventriculus to the rectum. Very few positive crest-derived cells were found in the esophagus. Injection of somites 1, 2, and 7 resulted in a smaller percentage of preparations with positive crest-derived cells and in a smaller number of positive crest-derived cells, which were confined to the fore and midgut. The gizzard was the gut region most frequently containing labeled cells and the rectum was the region least frequently containing such cells. This suggests that the number of crest cells available for colonization of the gut decreases as the distance from the gizzard increases. We conclude that the region of the neuroaxis between somites 3-6 is the major source of crest cells to the gut and that crest cells from different segments of the neuroaxis do not appear to be segregated to different regions of the gut. 0 1994 Wiley-Liss, Inc. 0 1994 WILEY-LISS, INC
Carcinogenesis, 2003
The role of three major Ras downstream effector pathways in the induction of mammary cancer was s... more The role of three major Ras downstream effector pathways in the induction of mammary cancer was studied using an in situ mammary ductal gene delivery model. Replicationdefective retroviral vectors were used to infect endogenous rat mammary epithelial cells with three individual Ras effector loop mutants, each of which transduces its signal through a different Ras effector pathway (Raf, PI3K or RalGDS). Several groups have used Ras effector loop mutants in cultured cells, clearly characterizing the signaling specificity of each over a wide range of cell lines and conditions. Each of the three Ras effector loop mutations impairs Ras for neoplastic transformation of immortal cell lines in culture. In contrast, when evaluated in vivo by infecting endogenous rat mammary epithelial cells in situ with retroviral vectors, we find that codon 12 mutant activated V12-Ras and all three V12-Ras effector loop mutants individually induce mammary carcinomas. Most notably, a Ras effector loop mutant that lacks affinity with PI3K and RalGDS but retains affinity with Raf (E38-V12-Ras) is relatively similar in potency to V12-Ras for mammary carcinoma induction. Two other Ras effector loop mutants, each lacking affinity with Raf, one retaining affinity with PI3K (C40-V12-Ras), the other with RalGDS (G37-V12-Ras), resulted in much longer tumor latency than E38-V12-Ras and V12-Ras and a reduced carcinoma frequency. Tumor latencies for V12-Ras, E38-V12-Ras, C40-V12-Ras and G37-V12-Ras were 4, 4, 11 and 12 weeks, respectively. We conclude that the Ras-Raf pathway can function independently of the Ras-PI3K and Ras-RalGDS pathways for rapid induction of rat mammary carcinomas, while Ras-PI3K and Ras-RalGDS pathways may also individually induce mammary carcinomas following a long latency.
Carcinogenesis, 2003
Mammary carcinogenesis induced through expression of activated Raf was investigated using a model... more Mammary carcinogenesis induced through expression of activated Raf was investigated using a model in which retroviral vectors were infused into the central ducts of rat mammary glands. This model allows efficient expression of experimental proteins in a small fraction of endogenous mammary epithelial cells in situ. We previously reported that Raf is the dominant oncogenic signaling pathway from activated Ras in rat mammary glands. We show here that mammary gland carcinogenesis is rapidly induced by the expression of c-Raf-1 kinase that is activated by N-terminal truncation (D-Raf). Interestingly, targeting Raf to the plasma membrane via C-terminal fusion with Ras membrane localization signals (Raf-Caax) induces Raf kinase activity that transforms 3T3 cells more frequently than D-Raf, yet in situ expression of Raf-Caax does not induce mammary carcinomas. To investigate these contrasting results and begin elucidating the mechanisms of Raf-induced mammary carcinogenesis, we combined both activating mutations (N-terminal truncation and C-terminal membrane localization motifs) in one Raf construct (D-Raf-Caax). While D-Raf-Caax transforms 3T3 cells more efficiently than D-Raf or Raf-Caax, in situ expression of D-Raf-Caax does not induce carcinomas in vivo, demonstrating that lipid modification on the C-terminus of D-Raf negates its oncogenic potential in rat mammary gland.
Archives of General Psychiatry, 2012
Context: Emotion regulation deficits figure prominently in generalized anxiety disorder (GAD) and... more Context: Emotion regulation deficits figure prominently in generalized anxiety disorder (GAD) and in other anxiety and mood disorders. Research examining emotion regulation and top-down modulation has implicated reduced coupling of the amygdala with prefrontal cortex and anterior cingulate cortex, suggesting altered frontolimbic white matter connectivity in GAD.
... Amygdala hypoactivity to aversive pictures and sustained pupil hyporesponsivity following aff... more ... Amygdala hypoactivity to aversive pictures and sustained pupil hyporesponsivity following affective stimulus presentations characterize GAD patients/ chronic worriers (Oathes et al., 2007; Oathes, Siegle, & Ray, submitted). ... Oathes, Siegle, & Ray (submitted). ...
Molecular Psychiatry
Some individuals are endowed with a biology that renders them more reactive to novelty and potent... more Some individuals are endowed with a biology that renders them more reactive to novelty and potential threat. When extreme, this
anxious temperament (AT) confers elevated risk for the development of anxiety, depression and substance abuse. These disorders
are highly prevalent, debilitating and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and
young monkeys and mechanistic work demonstrates that the central (Ce) nucleus of the amygdala is an important substrate.
Although it is widely believed that the flow of information across the structural network connecting the Ce nucleus to other brain
regions underlies primates’ capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly
understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting
children with anxiety disorders to identify an evolutionarily conserved pattern of functional connectivity relevant to early-life
anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex,
a region thought to play a central role in the control of cognition and emotion, and the Ce nucleus was associated with increased
anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography imaging
provided evidence that elevated Ce nucleus metabolism statistically mediates the association between prefrontal-amygdalar
connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety
and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety.
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Papers by Daniel McFarlin
anxious temperament (AT) confers elevated risk for the development of anxiety, depression and substance abuse. These disorders
are highly prevalent, debilitating and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and
young monkeys and mechanistic work demonstrates that the central (Ce) nucleus of the amygdala is an important substrate.
Although it is widely believed that the flow of information across the structural network connecting the Ce nucleus to other brain
regions underlies primates’ capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly
understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting
children with anxiety disorders to identify an evolutionarily conserved pattern of functional connectivity relevant to early-life
anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex,
a region thought to play a central role in the control of cognition and emotion, and the Ce nucleus was associated with increased
anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography imaging
provided evidence that elevated Ce nucleus metabolism statistically mediates the association between prefrontal-amygdalar
connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety
and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety.
anxious temperament (AT) confers elevated risk for the development of anxiety, depression and substance abuse. These disorders
are highly prevalent, debilitating and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and
young monkeys and mechanistic work demonstrates that the central (Ce) nucleus of the amygdala is an important substrate.
Although it is widely believed that the flow of information across the structural network connecting the Ce nucleus to other brain
regions underlies primates’ capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly
understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting
children with anxiety disorders to identify an evolutionarily conserved pattern of functional connectivity relevant to early-life
anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex,
a region thought to play a central role in the control of cognition and emotion, and the Ce nucleus was associated with increased
anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography imaging
provided evidence that elevated Ce nucleus metabolism statistically mediates the association between prefrontal-amygdalar
connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety
and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety.