Clas Linnman

Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats.

BACKGROUND Men and women differ in their ability to extinguish fear. Fear extinction requires the activation of brain regions, including the ventromedial prefrontal cortex (vmPFC) and amygdala. Could estradiol modulate the activity of these brain regions during fear extinction? METHODS All rat experiments were conducted in naturally cycling females. Rats underwent fear conditioning on Day 1. On Day 2, they underwent extinction training during the metestrus phase of the cycle (low estrogen and progesterone). Extinction recall was assessed on Day 3. Systemic injections of estrogen receptor-beta and -alpha agonists and of estradiol were administered at different time points to assess their influence on extinction consolidation and c-Fos expression in the vmPFC and amygdala. In parallel, healthy naturally cycling women underwent an analogous fear conditioning extinction training in a 3T functional magnetic resonance scanner. Measurement of their estradiol levels and skin conductance responses were obtained throughout the experiment. RESULTS In female rats, administration of the estrogen-receptor beta (but not alpha) agonist facilitated extinction recall. Immediate (but not delayed) postextinction training administration of estradiol facilitated extinction memory consolidation and increased c-Fos expression in the vmPFC while reducing it in the amygdala. In parallel, natural variance in estradiol in premenopausal cycling women modulated vmPFC and amygdala reactivity and facilitated extinction recall. CONCLUSIONS We provide translational evidence that demonstrates the influence of endogenous and exogenous estradiol on the fear extinction network. Our data suggest that womens endogenous hormonal status should be considered in future neurobiological research related to anxiety and mood disorders.

Neuroimaging of the Periaqueductal Gray: State of the Field

This review and meta-analysis aims at summarizing and integrating the human neuroimaging studies that report periaqueductal gray (PAG) involvement; 250 original manuscripts on human neuroimaging of the PAG were identified. A narrative review and meta-analysis using activation likelihood estimates is included. Behaviors covered include pain and pain modulation, anxiety, bladder and bowel function and autonomic regulation. Methods include structural and functional magnetic resonance imaging, functional connectivity measures, diffusion weighted imaging and positron emission tomography. Human neuroimaging studies in healthy and clinical populations largely confirm the animal literature indicating that the PAG is involved in homeostatic regulation of salient functions such as pain, anxiety and autonomic function. Methodological concerns in the current literature, including resolution constraints, imaging artifacts and imprecise neuroanatomical labeling are discussed, and future directions are proposed. A general conclusion is that PAG neuroimaging is a field with enormous potential to translate animal data onto human behaviors, but with some growing pains that can and need to be addressed in order to add to our understanding of the neurobiology of this key region.

A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety

Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

Altered Processing of Contextual Information during Fear Extinction in PTSD: An fMRI Study

Medial prefrontal cortical areas have been hypothesized to underlie altered contextual processing in posttraumatic stress disorder (PTSD). We investigated brain signaling of contextual information in this disorder. Eighteen PTSD subjects and 16 healthy trauma‐exposed subjects underwent a two‐day fear conditioning and extinction paradigm. On day 1, within visual context A, a conditioned stimulus (CS) was followed 60% of the time by an electric shock (conditioning). The conditioned response was then extinguished (extinction learning) in context B. On day 2, recall of the extinction memory was tested in context B. Skin conductance response (SCR) and functional magnetic resonance imaging (fMRI) data were collected during context presentations. There were no SCR group differences in any context presentation. Concerning fMRI data, during late conditioning, when context A signaled danger, PTSD subjects showed dorsal anterior cingulate cortical (dACC) hyperactivation. During early extinction, when context B had not yet fully acquired signal value for safety, PTSD subjects still showed dACC hyperactivation. During late extinction, when context B had come to signal safety, they showed ventromedial prefrontal cortex (vmPFC) hypoactivation. During early extinction recall, when context B signaled safety, they showed both vmPFC hypoactivation and dACC hyperactivation. These findings suggest that PTSD subjects show alterations in the processing of contextual information related to danger and safety. This impairment is manifest even prior to a physiologically‐measured, cue‐elicited fear response, and characterized by hypoactivation in vmPFC and hyperactivation in dACC.

Abnormally high degree connectivity of the orbitofrontal cortex in obsessive-compulsive disorder.

IMPORTANCE Neurobiological models of obsessive-compulsive disorder (OCD) predict hyperactivity in brain circuits involving the orbitofrontal cortex and the basal ganglia, but it is unclear whether these areas are also characterized by altered brain network properties. OBJECTIVES To determine regions of abnormal degree connectivity in patients with OCD and to investigate whether connectivity measures are affected by antidepressant medication in OCD. DESIGN Case-control cross-sectional study using resting-state functional magnetic resonance imaging and a data-driven, model-free method to test for alterations in the degree of whole-brain, distant, and local connectivity in unmedicated patients with OCD compared with healthy controls. SETTING Outpatient clinic for OCD. PARTICIPANTS Twenty-three patients with OCD (12 women, 11 men) receiving no medication, 23 patients with OCD (14 women, 9 men) treated with antidepressant medication, and 2 equally sized control samples matched for age, sex, handedness, educational level, and IQ. MAIN OUTCOME MEASURES Statistical parametric maps testing the degree of distant and local functional connectivity of each voxel (hub analysis at voxel level) and OCD symptom severity. RESULTS Unmedicated patients with OCD showed greater distant connectivity in the orbitofrontal cortex and subthalamic nucleus and greater local connectivity in the orbitofrontal cortex and the putamen. Furthermore, distant connectivity of the orbitofrontal cortex and the putamen positively correlated with global OCD symptom severity. Medicated patients with OCD showed reduced local connectivity of the ventral striatum compared with the unmedicated patients. CONCLUSIONS AND RELEVANCE Consistent with neurobiological models of OCD, the orbitofrontal cortex and the basal ganglia are hyperconnected in unmedicated patients. The finding of distant connectivity alterations of the orbitofrontal cortex and the basal ganglia represents initial evidence of greater connections with distant cortical areas outside of corticostriatal circuitry. Furthermore, these data suggest that antidepressant medication may reduce connectivity within corticobasal ganglia-thalamo-cortical circuits in OCD.

The human amygdala and pain: Evidence from neuroimaging

The amygdala, a small deep brain structure involved in behavioral processing through interactions with other brain regions, has garnered increased attention in recent years in relation to pain processing. As pain is a multidimensional experience that encompasses physical sensation, affect, and cognition, the amygdala is well suited to play a part in this process. Multiple neuroimaging studies of pain in humans have reported activation in the amygdala. Here, we summarize these studies by performing a coordinate‐based meta‐analysis within experimentally induced and clinical pain studies using an activation likelihood estimate analysis. The results are presented in relation to locations of peak activation within and outside of amygdala subregions. The majority of studies identified coordinates consistent with human amygdala cytoarchitecture indicating reproducibility in neuroanatomical labeling across labs, analysis methods, and imaging modalities. Differences were noted between healthy and clinical pain studies: in clinical pain studies, peak activation was located in the laterobasal region, suggestive of the cognitive‐affective overlay present among individuals suffering from chronic pain; while the less understood superficial region of the amygdala was prominent among experimental pain studies. Taken together, these findings suggest several important directions for further research exploring the amygdalas role in pain processing. Hum Brain Mapp 35:527–538, 2014.

The Young Brain and Concussion: Imaging as a Biomarker for Diagnosis and Prognosis

Concussion (mild traumatic brain injury (mTBI)) is a significant pediatric public health concern. Despite increased awareness, a comprehensive understanding of the acute and chronic effects of concussion on central nervous system structure and function remains incomplete. Here we review the definition, epidemiology, and sequelae of concussion within the developing brain, during childhood and adolescence, with current data derived from studies of pathophysiology and neuroimaging. These findings may contribute to a better understanding of the neurological consequences of traumatic brain injuries, which in turn, may lead to the development of brain biomarkers to improve identification, management and prognosis of pediatric patients suffering from concussion.

Resting amygdala and medial prefrontal metabolism predicts functional activation of the fear extinction circuit.

OBJECTIVE Individual differences in a persons ability to control fear have been linked to activation in the dorsal anterior cingulate cortex, the ventromedial prefrontal cortex, and the amygdala. This study investigated whether functional variance in this network can be predicted by resting metabolism in these same regions. METHOD The authors measured resting brain metabolism in healthy volunteers with positron emission tomography using [18F]fluorodeoxyglucose. This was followed by a 2-day fear conditioning and extinction training paradigm using functional MRI to measure brain activation during fear extinction and recall. The authors used skin conductance response to index conditioned responding, and they used resting metabolism in the amygdala, the dorsal anterior cingulate cortex, and the ventromedial prefrontal cortex to predict responses during fear extinction and extinction recall. RESULTS During extinction training, resting amygdala metabolism positively predicted activation in the ventromedial prefrontal cortex and negatively predicted activation in the dorsal anterior cingulate cortex. In contrast, during extinction recall, resting amygdala metabolism negatively predicted activation in the ventromedial prefrontal cortex and positively predicted activation in the dorsal anterior cingulate cortex. In addition, resting metabolism in the dorsal anterior cingulate cortex predicted fear expression (as measured by skin conductance response) during extinction recall. CONCLUSIONS Resting brain metabolism predicted neuronal reactivity and skin conductance changes associated with the recall of the fear extinction memory.

Unconditioned responses and functional fear networks in human classical conditioning

Human imaging studies examining fear conditioning have mainly focused on the neural responses to conditioned cues. In contrast, the neural basis of the unconditioned response and the mechanisms by which fear modulates inter-regional functional coupling have received limited attention. We examined the neural responses to an unconditioned stimulus using a partial-reinforcement fear conditioning paradigm and functional MRI. The analysis focused on: (1) the effects of an unconditioned stimulus (an electric shock) that was either expected and actually delivered, or expected but not delivered, and (2) on how related brain activity changed across conditioning trials, and (3) how shock expectation influenced inter-regional coupling within the fear network. We found that: (1) the delivery of the shock engaged the red nucleus, amygdale, dorsal striatum, insula, somatosensory and cingulate cortices, (2) when the shock was expected but not delivered, only the red nucleus, the anterior insular and dorsal anterior cingulate cortices showed activity increases that were sustained across trials, and (3) psycho-physiological interaction analysis demonstrated that fear led to increased red nucleus coupling to insula but decreased hippocampus coupling to the red nucleus, thalamus and cerebellum. The hippocampus and the anterior insula may serve as hubs facilitating the switch between engagement of a defensive immediate fear network and a resting network.

Sex similarities and differences in pain-related periaqueductal gray connectivity

Summary Pain induces changes in the functional connectivity between the periaqueductal gray and the cingulate, and, in men more than women, connectivity changes to the amygdala. Abstract This study investigated sex similarities and differences in pain‐related functional connectivity in 60 healthy subjects. We used functional magnetic resonance imaging and psychophysiological interaction analysis to investigate how exposure to low vs high experimental pain modulates the functional connectivity of the periaqueductal gray (PAG). We found no sex differences in pain thresholds, and in both men and women, the PAG was more functionally connected with the somatosensory cortex, the supplemental motor area, cerebellum, and thalamus during high pain, consistent with anatomic predictions. Twenty‐six men displayed a pain‐induced increase in PAG functional connectivity with the amygdala caudate and putamen that was not observed in women. In an extensive literature search, we found that female animals have been largely overlooked when the connections between the PAG and the amygdala have been described, and that women are systematically understudied with regard to endogenous pain inhibition. Our results emphasize the importance of including both male and female subjects when studying basic mechanisms of pain processing, and point toward a possible sex difference in endogenous pain inhibition.