Mark Rijpkema

Identification of common variants associated with human hippocampal and intracranial volumes

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimers disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7).

Stress-related noradrenergic activity prompts large-scale neural network reconfiguration

Acute stress leads to reorganization of large-scale neural network connectivity in the brain that is driven by noradrenaline. Acute stress shifts the brain into a state that fosters rapid defense mechanisms. Stress-related neuromodulators are thought to trigger this change by altering properties of large-scale neural populations throughout the brain. We investigated this brain-state shift in humans. During exposure to a fear-related acute stressor, responsiveness and interconnectivity within a network including cortical (frontoinsular, dorsal anterior cingulate, inferotemporal, and temporoparietal) and subcortical (amygdala, thalamus, hypothalamus, and midbrain) regions increased as a function of stress response magnitudes. β-adrenergic receptor blockade, but not cortisol synthesis inhibition, diminished this increase. Thus, our findings reveal that noradrenergic activation during acute stress results in prolonged coupling within a distributed network that integrates information exchange between regions involved in autonomic-neuroendocrine control and vigilant attentional reorienting.

Method for quantitative mapping of dynamic MRI contrast agent uptake in human tumors.

A method is presented for the acquisition and analysis of dynamic contrast‐enhanced (DCE) MRI data, focused on the characterization of tumors in humans. Gadolinium (Gd) contrast was administered by bolus injection, and its effect was monitored in time by fast T1‐weighted MRI. A simple algorithm was developed for automatic extraction of the arterial input function (AIF) from the DCE‐MRI data. This AIF was used in the pixelwise pharmacokinetic determination of physiological vascular parameters in normal and tumor tissue. Maps were reconstructed to show the spatial distribution of parameter values. To test the reproducibility of the method 11 patients with different types of tumors were measured twice, and the rate of contrast agent uptake in the tumor was calculated. The results show that normalizing the DCE‐MRI data using individual coregistered AIFs, instead of one common AIF for all patients, substantially reduces the variation between successive measurements. It is concluded that the proposed method enables the reproducible assessment of contrast agent uptake rates. J. Magn. Reson. Imaging 2001;14:457–463.

Shift from Hippocampal to Neocortical Centered Retrieval Network with Consolidation

The standard model of system-level consolidation posits that the hippocampus is part of a retrieval network for recent memories. According to this theory, the memories are gradually transferred to neocortical circuits with consolidation, where the connections within this circuit grow stronger and reorganized so that redundant and/or contextual details may be lost. Thus, remote memories are based on neocortical networks and can be retrieved independently of the hippocampus. To test this model, we measured regional brain activity and connectivity during retrieval with functional magnetic resonance imaging. Subjects were trained on two sets of face-location association and were tested with two different delays, 15 min and 24 h including a whole night of sleep. We hypothesized that memory traces of the locations associated with specific faces will be linked through the hippocampus for the retrieval of recently learned association, but with consolidation, the activity and the functional connectivity between the neocortical areas will increase. We show that posterior hippocampal activity related to high-confidence retrieval decreased and neocortical activity increased with consolidation. Moreover, the connectivity between the hippocampus and the neocortical regions decreased and in turn, cortico-cortical connectivity between the representational areas increased. The results provide mechanistic support for a two-level process of the declarative memory system, involving initial representation of new associations in a network including the hippocampus and subsequent consolidation into a predominantly neocortical network.

Combined quantitative dynamic contrast-enhanced MR imaging and (1)H MR spectroscopic imaging of human prostate cancer.

To differentiate prostate carcinoma from healthy peripheral zone and central gland using quantitative dynamic contrast‐enhanced (DCE) magnetic resonance (MR) imaging and two‐dimensional 1H MR spectroscopic imaging (MRSI) combined into one clinical protocol.

Retrieval of Associative Information Congruent with Prior Knowledge Is Related to Increased Medial Prefrontal Activity and Connectivity

We remember information that is congruent instead of incongruent with prior knowledge better, but the underlying neural mechanisms related to this enhancement are still relatively unknown. Recently, this memory enhancement due to a prior schema has been suggested to be based on rapid neocortical assimilation of new information, related to optimized encoding and consolidation processes. The medial prefrontal cortex (mPFC) is thought to be important in mediating this process, but its role in retrieval of schema-consistent information is still unclear. In this study, we regarded multisensory congruency with prior knowledge as a schema and used this factor to probe retrieval of consolidated memories either consistent or inconsistent with prior knowledge. We conducted a visuotactile learning paradigm in which participants studied visual motifs randomly associated with word–fabric combinations that were either congruent or incongruent with common knowledge. The next day, participants were scanned using functional magnetic resonance imaging while their memory was tested. Congruent associations were remembered better than incongruent ones. This behavioral finding was parallelized by stronger retrieval-related activity in and connectivity between medial prefrontal and left somatosensory cortex. Moreover, we found a positive across-subject correlation between the connectivity enhancement and the behavioral congruency effect. These results show that successful retrieval of congruent compared to incongruent visuotactile associations is related to enhanced processing in an mPFC–somatosensory network, and support the hypothesis that new information that fits a preexisting schema is more rapidly assimilated in neocortical networks, a process that may be mediated, at least in part, by the mPFC.

Striatal Dopamine Mediates the Interface between Motivational and Cognitive Control in Humans: Evidence from Genetic Imaging

Dopamine has been hypothesized to provide the basis for the interaction between motivational and cognitive control. However, there is no evidence for this hypothesis in humans. We fill this gap by using fMRI, a novel behavioral paradigm and a common polymorphism in the DAT1 gene (SLC6A3). Carriers of the 9-repeat (9R) allele of a 40 base pair repeat polymorphism in the 3′ untranslated region of DAT1, associated with high striatal dopamine, showed greater activity in the ventromedial striatum during reward anticipation than homozygotes for the 10-repeat allele, replicating previous genetic imaging studies. The crucial novel finding is that 9R carriers also exhibited a greater influence of anticipated reward on switch costs, as well as greater activity in the dorsomedial striatum during task switching in anticipation of high reward relative to low reward. These data establish a crucial role for human striatal dopamine in the modulation of cognitive flexibility by reward anticipation, thus, elucidating the neurochemical mechanism of the interaction between motivation and cognitive control.

Amygdala volume marks the acute state in the early course of depression.

BACKGROUND The amygdala and hippocampus play a key role in the neural circuitry mediating depression. It remains unclear how much structural and functional changes of amygdala and hippocampus reflect the acute state of depression or an underlying neurobiological trait marker of depression. METHODS High-resolution anatomical images were acquired in 20 medication-naïve major depressive disorder (MDD) patients with a current first episode, 20 medication-free patients recovered from a first episode of MDD, and 20 healthy control subjects that were matched for age, gender, and level of education. Manual volumetry of amygdala and hippocampus was performed on coronal images. Volumetric measurements of brain volume and intracranial volume were acquired with automatic segmentation procedures. RESULTS Both amygdalae were significantly enlarged in currently depressed patients, whereas there was no significant difference between recovered patients and control subjects. The amygdala enlargement correlated positively with the severity of depressive state but with no other clinical or neuropsychological variable. The hippocampal volume did not differ between groups. CONCLUSIONS A state related increase of amygdala volume can be detected early in the course of MDD. Neurotoxic effects might account for the fact that state-related amygdala enlargement has not been found in recurrent depression with relative long illness duration.

Effects of breathing a hyperoxic hypercapnic gas mixture on blood oxygenation and vascularity of head-and-neck tumors as measured by magnetic resonance imaging.

PURPOSE For head-and-neck tumors, breathing a hyperoxic hypercapnic gas mixture and administration of nicotinamide has been shown to result in a significantly improved tumor response to accelerated radiotherapy (ARCON, Accelerated Radiotherapy with CarbOgen and Nicotinamide). This may be caused by improved tumor oxygenation, possibly mediated by vascular effects. In this study, both blood oxygenation and vascular effects of breathing a hyperoxic hypercapnic gas mixture (98% O2 + 2% CO2) were assessed by magnetic resonance imaging (MRI) in patients with head-and-neck tumors. METHODS AND MATERIALS Tumor vascularity and oxygenation were investigated by dynamic gadolinium contrast-enhanced MRI and blood oxygen level dependent (BOLD) MRI, respectively. Eleven patients with primary head-and-neck tumors were each measured twice; with and without breathing the hyperoxic hypercapnic gas mixture. RESULTS BOLD MR imaging revealed a significant increase of the MRI time constant of transverse magnetization decay (T2*) in the tumor during hypercapnic hyperoxygenation, which correlates to a decrease of the deoxyhemoglobin concentration. No changes in overall tumor vascularity were observed, as measured by the gadolinium contrast uptake rate in the tumor. CONCLUSION Breathing a hyperoxic hypercapnic gas mixture improves tumor blood oxygenation in patients with head-and-neck tumors, which may contribute to the success of the ARCON therapy.

BDNF Val66Met genotype modulates the effect of childhood adversity on subgenual anterior cingulate cortex volume in healthy subjects

According to the neurotrophic hypothesis of depression, stress can lead to brain atrophy by modifying brain-derived neurotrophic factor (BDNF) levels. Given that BDNF secretion is affected by a common polymorphism (rs6265, Val66Met), which also is associated with depression, we investigated whether this polymorphism modifies the effect of childhood adversity (CA) on local gray matter (GM) volume in depression-relevant brain regions, using data from two large cohorts of healthy subjects. We included 568 healthy volunteers (aged 18–50 years, 63% female) in our study, for whom complete data were available, with magnetic resonance imaging data at 1.5 Tesla (N=275) or 3 Tesla (N=293). We used a whole brain optimized voxel-based morphometry (VBM) approach assessing genotype-dependent GM differences, with focus on the amygdala, hippocampus and medial prefrontal cortex (PFC; including anterior cingulate cortex (ACC) and orbitomedial PFC). CA was assessed using a validated questionnaire. In both cohorts, we found that BDNF methionine (Met)-allele carriers with a history of CA had significantly less GM in subgenual ACC (P<0.05) compared with Met-allele carriers without CA and Val/Val homozygotes with CA. No differences were found in hippocampus, amygdala and orbitomedial PFC. On the basis of our findings, we conclude that BDNF Met-allele carriers are particularly sensitive to CA. Given the key role of the subgenual ACC in emotion regulation, this finding provides an important mechanistic link between stress and BDNF on one hand and mood impairments on the other hand.