Cortical and thalamic influences on striatal involvement in instructed, serial reversal learning; implications for the organisation of flexible behaviour.

Cognitive flexibility is essential for enabling an individual to respond adaptively to changes in their environment. Evidence from human and animal research suggests that the control of cognitive flexibility is dependent on an array of neural architecture. Cortico-basal ganglia circuits have long been implicated in cognitive flexibility. In particular, the role of the striatum is pivotal, acting as an integrative hub for inputs from the prefrontal cortex and thalamus, and modulation by dopamine and acetylcholine. Striatal cholinergic modulation has been implicated in the flexible control of behaviour, driven by input from the centromedian-parafascicular nuclei of the thalamus. However, the role of this system in humans is not clearly defined as much of the current literature is based on animal work. Here, we aim to investigate the roles corticostriatal and thalamostriatal connectivity in serial reversal learning. Functional connectivity between the left centromedian-parafascicular nuclei and the associative dorsal striatum was significantly increased for negative feedback compared to positive feedback. Similar differences in functional connectivity were observed for the right lateral orbitofrontal cortex, but these were localised to when participants switched to using an alternate response strategy following reversal. These findings suggest that connectivity between the centromedian-parafascicular nuclei and the striatum may be used to generally identify potential changes in context based on negative outcomes, and the effect of this signal on striatal output may be influenced by connectivity between the lateral orbitofrontal cortex and the striatum.

Orbitofrontal cortex contributes to the comparison of values underlying economic choices

Economic choices between goods entail the computation and comparison of subjective values. Previous studies examined neuronal activity in the orbitofrontal cortex (OFC) of monkeys choosing between different types of juices. Three groups of neurons were identified: offer value cells encoding the value of individual offers, chosen juice cells encoding the identity of the chosen juice, and chosen value cells encoding the value of the chosen offer. The encoded variables capture both the input (offer value) and the output (chosen juice, chosen value) of the decision process, suggesting that values are compared within OFC. Recent work demonstrates that choices are causally linked to the activity of offer value cells. Conversely, the hypothesis that OFC contributes to value comparison has not been confirmed. Here we show that weak electrical stimulation of OFC specifically disrupts value comparison without altering offer values. This result implies that neuronal populations in OFC participate in the decision process.

Epigenetic Silencing of OR and TAS2R Genes Expression in Human Orbitofrontal Cortex At Early Stages of Sporadic Alzheimer’s Disease

Modulation of brain olfactory (OR) and taste receptors (TASR) expression was recently reported in neurological diseases. We explored the possible expression and regulation of selected OR and TASR genes in human orbitofrontal cortex of sporadic Alzheimer’s disease (AD) and found that these are expressed and markedly downregulated at early stages. The expression pattern did not follow disease progression suggesting regulation through epigenetic mechanisms. We found an increase of global H3K9me3 levels and substantial enrichment of this repressive signature at ORs and TAS2Rs proximal promoter at early stages, ultimately lost at advanced stages. By mass spectrometry-based proteomic and further validation, we found that H3K9me3 interacts with MeCP2 at early stages and that this protein is increased in sporadic AD. Findings suggest MeCP2 might be implicated in OR and TAS2R genes expression regulation through interaction with H3K9me3, and as an early event, it may uncover a novel etiopathogenetic mechanism of sporadic AD.

Ruminative reflection is associated with anticorrelations between the orbitofrontal cortex and the default mode network in depression: implications for repetitive transcranial magnetic stimulation

Patients with depression who ruminate repeatedly focus on depressive thoughts; however, there are two cognitive subtypes of rumination, reflection and brooding, each associated with different prognoses. Reflection involves problem-solving and is associated with positive outcomes, whereas brooding involves passive, negative, comparison with other people and is associated with poor outcomes. Rumination has also been related to atypical functional hyperconnectivity between the default mode network and subgenual prefrontal cortex. Repetitive pulse transcranial magnetic stimulation of the prefrontal cortex has been shown to alter functional connectivity, suggesting that the abnormal connectivity associated with rumination could potentially be altered. This study examined potential repetitive pulse transcranial magnetic stimulation prefrontal cortical targets that could modulate one or both of these rumination subtypes. Forty-three patients who took part in a trial of repetitive pulse transcranial magnetic stimulation completed the Rumination Response Scale questionnaire and resting-state functional magnetic resonance imaging. Seed to voxel functional connectivity analyses identified an anticorrelation between the left lateral orbitofrontal cortex (−44, 26, −8; k = 172) with the default mode network-subgenual region in relation to higher levels of reflection. Parallel analyses were not significant for brooding or the RRS total score. These findings extend previous studies of rumination and identify a potential mechanistic model for symptom-based neuromodulation of rumination.

Decreased activity of piriform cortex and orbitofrontal hyperactivation in Usher Syndrome, a human disorder of ciliary dysfunction

Usher syndrome (USH) is a condition characterized by ciliary dysfunction leading to retinal degeneration and hearing/vestibular loss. Putative olfactory deficits in humans have been documented at the psychophysical level and remain to be proven at the neurophysiological level. Thus, we aimed to study USH olfactory impairment using functional magnetic resonance imaging. We analyzed differences in whole-brain responses between 27 USH patients and 26 healthy participants during an olfactory detection task with a bimodal odorant (n-butanol). The main research question was whether between-group differences could be identified using a conservative whole-brain approach and in a ROI-based approach in key olfactory brain regions. Results indicated higher olfactory thresholds in USH patients, thereby confirming the hypothesis of reduced olfactory acuity. Importantly, we found decreased BOLD activity for USH patients in response to odorant stimulation in the right piriform cortex, while right orbitofrontal cortex showed increased activity. We also found decreased activity in other higher-level regions in a whole brain approach. We suggest that the hyper activation in the orbitofrontal cortex possibly occurs as a compensatory mechanism after the under-recruitment of the piriform cortex. This study suggests that olfactory deficits in USH can be objectively assessed using functional neuroimaging which reveals differential patterns of activity both in low- and high-level regions of the olfactory network.