Investigating Intra-Individual Networks of Response Inhibition and Interference Resolution using 7T MRI.

Response inhibition and interference resolution are often considered subcomponents of an overarching inhibition system that utilizes the so-called cortico-basal-ganglia loop. Up until now, most previous functional magnetic resonance imaging (fMRI) literature has compared the two using between-subject designs, pooling data in the form of a meta-analysis or comparing different groups. Here, we investigate the overlap of activation patterns underlying response inhibition and interference resolution on a within-subject level, using ultra-high field MRI. In this model-based study, we furthered the functional analysis with cognitive modelling techniques to provide a more in-depth understanding of behaviour. We applied the stop-signal task and multi-source interference task to measure response inhibition and interference resolution, respectively. Our results lead us to conclude that these constructs are rooted in anatomically distinct brain areas and provide little evidence for spatial overlap. Across the two tasks, common BOLD responses were observed in the inferior frontal gyrus and anterior insula. Interference resolution relied more heavily on subcortical components, specifically nodes of the commonly referred to indirect and hyperdirect pathways, as well as the anterior cingulate cortex, and pre-supplementary motor area. Our data indicated that orbitofrontal cortex activation is specific to response inhibition. Our model-based approach provided evidence for the dissimilarity in behavioural dynamics between the two tasks. The current work exemplifies the importance of reducing inter-individual variance when comparing network patterns and the value of UHF-MRI for high resolution functional mapping.

Central and peripheral effects of thyroid hormone signalling in the control of energy metabolism.

Increasing evidence points towards a role for thyroid hormone signalling in the central nervous system with respect to the development of symptoms of thyroid disease, in addition to the well-known peripheral effects of thyroid hormone. Thyroid hormone affects target tissues directly via thyroid hormone receptors, but also indirectly through effects on the integration of the sympathetic signal in target tissues. The present review discusses these pathways and the evidence for a third pathway, that is effects of thyroid hormone on the pre-autonomic neurones in the central nervous system. The pre-autonomic neurones reside in the hypothalamus in brain nuclei such as the paraventricular nucleus of the hypothalamus where thyroid hormone receptor isoforms are expressed. Recent data from studies in transgenic mice implicate a role for thyroid hormone receptor alpha 1 in the modulation of sympathetic signalling to target tissues, thereby affecting both glucose and lipid metabolism. Focal stimulation of hypothalamic nuclei expressing thyroid hormone receptors and selective liver denervation experiments in rats have provided further evidence indicating that the metabolic changes observed during hyperthyroidism are not only a result of increased thyroid hormone signalling in the periphery, but also, at least in part, result from altered signalling in thyroid hormone sensitive neurones.

Induction of type 3 deiodinase activity in inflammatory cells of mice with chronic local inflammation.

During illness, changes in thyroid hormone metabolism occur, so-called nonthyroidal illness (NTI). NTI has been characterized by a fall of serum T(3) due to decreased extrathyroidal conversion of T(4) into T(3) by liver type 1 deiodinase (D1), without an increase in serum TSH. Type 3 deiodinase (D3) was thought not to play an important role during NTI, but recently it has been shown that D3 activity is up-regulated in liver and skeletal muscle of critically ill patients related to hypoxia. We studied D3 gene expression and activity in liver and muscle/subcutis of mice during illness, which was induced by two different stimuli: bacterial endotoxin (lipopolysaccharide) administration, resulting in an acute systemic response, and a turpentine injection in each hindlimb, resulting in a local sc abscess. Lipopolysaccharide induced a rapid decrease in liver D1 and D3 activity but not skeletal muscle of hindlimb. In contrast, local inflammation induced by turpentine did not decrease liver D1 and D3 activity but increased markedly D3 activity in the muscle/subcutis sample containing the abscess, associated with strongly increased IL-1beta and IL-6 mRNA expression. Inflammatory cells, surrounding the abscess showed D3 and T(3)-transporter monocarboxylate transporter-8 immunoreactivity, whereas muscle cells did not show any immunoreactivity. In conclusion, local inflammation strongly induces D3 activity in inflammatory cells, especially in invading polymorphonuclear granulocytes, suggesting enhanced local degradation of T(3).

Glucocorticoids decrease thyrotropin-releasing hormone messenger ribonucleic acid expression in the paraventricular nucleus of the human hypothalamus.

The way glucocorticoids affect TRH mRNA expression in the paraventricular nucleus of the hypothalamus is still unclear. In view of its relevance for Cushing's syndrome and depression, we measured TRH mRNA expression in human hypothalami obtained at autopsy by means of quantitative TRH mRNA in situ hybridization. In corticosteroid-treated subjects (n = 10), TRH mRNA hybridization signal was decreased as compared with matched control subjects (n = 10) (Mann-Whitney U test, P = 0.02). By inference, hypercortisolism as present in patients with Cushing's syndrome or major depression may contribute to lower serum TSH or symptoms of depression by lowering hypothalamic TRH expression.

Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice.

During illness, major changes in thyroid hormone metabolism and regulation occur; these are collectively known as non-thyroidal illness and are characterized by decreased serum triiodothyronine (T(3)) and thyroxine (T(4)) without an increase in serum TSH. Whether alterations in the central part of the hypothalamus-pituitary-thyroid (HPT) axis precede changes in peripheral thyroid hormone metabolism instead of vice versa, or occur simultaneously, is presently unknown. We therefore studied the time-course of changes in thyroid hormone metabolism in the HPT axis of mice during acute illness induced by bacterial endotoxin (lipopolysaccharide; LPS).LPS rapidly induced interleukin-1beta mRNA expression in the hypothalamus, pituitary, thyroid and liver. This was followed by almost simultaneous changes in the pituitary (decreased expression of thyroid receptor (TR)-beta2, TSHbeta and 5'-deiodinase (D1) mRNAs), the thyroid (decreased TSH receptor mRNA) and the liver (decreased TRbeta1 and D1 mRNA). In the hypothalamus, type 2 deiodinase mRNA expression was strongly increased whereas preproTRH mRNA expression did not change after LPS. Serum T(3) and T(4) fell only after 24 h. Our results suggested almost simultaneous involvement of the whole HPT axis in the downregulation of thyroid hormone metabolism during acute illness.

The hypothalamic-pituitary-thyroid axis in critical illness.

In severe illness, profound changes occur in the hypothalamic-pituitary-thyroid axis. The observed decrease in serum concentration of both thyroid hormones and thyrotropin (TSH) are not compatible with a negative feedback loop and suggest a major change in setpoint regulation of the hypothalamic-pituitary-thyroid axis. This is supported by post mortem studies showing a decreased expression of thyrotropin-releasing hormone in the hypothalamic paraventricular nucleus of patients with a decreased serum T3 level. In critical illness, serum T3 may even become undetectable without giving rise to an elevated concentration of serum TSH. It is currently not clearly established whether this reflects an adaptation of the organism to illness or instead a potentially harmful condition leading to hypothyroidism at tissue level. There is thus a need for randomized clinical trials in critically ill patients to investigate whether they may benefit from a normalization of thyroid hormone concentration. Recent clinical studies in these patients involving the administration of hypothalamic peptides open up new ways of achieving this.