Pramipexole Enhances Reward Learning by Preserving Value Estimates

Background: Dopamine D2-like receptor agonists show promise as treatments for depression. They are thought to act by altering how individuals learn from rewarding experiences. However, the nature of these reward learning alterations, and the mechanisms by which they are produced is not clear. Reinforcement learning accounts describe three distinct processes that may produce similar changes in reward learning behaviour; increased reward sensitivity, increased inverse decision temperature and decreased value decay. As these processes produce equivalent effects on behaviour, arbitrating between them requires measurement of how expectations and prediction errors are altered. In the present study, we characterised the behavioural effects of a sustained 2-week course of the D2/3/4 receptor agonist pramipexole on reward learning and used fMRI measures of expectation and prediction error to assess which of these three mechanistic processes were responsible for the behavioural effects. Methods: 40 healthy volunteers (Age: 18-43, 50% female) were randomly allocated to receive either two weeks of pramipexole (titrated to 1mg/day) or placebo in a double-blind, between subject design. Participants completed a probabilistic instrumental learning task, in which stimuli were associated with either rewards or losses, before the pharmacological intervention and twice between days 12-15 of the intervention (once with and once without fMRI). Both asymptotic choice accuracy, and a reinforcement learning model, were used to assess reward learning. Results: Behaviourally, pramipexole specifically increased choice accuracy in the reward condition, with no effect in the loss condition. Pramipexole increased the BOLD response in the orbital frontal cortex during the expectation of win trials but decreased the BOLD response to reward prediction errors in the ventromedial prefrontal cortex. This pattern of results indicates that pramipexole enhances choice accuracy by reducing the decay of estimated values during reward learning. Conclusions: The D2-like receptor agonist pramipexole enhances reward learning by preserving learned values. This is a plausible candidate mechanism for pramipexoles observed anti-depressant effect.

Combining ultra-high-field fMRI adaptation and computational modelling to estimate neuronal frequency selectivity in human auditory cortex

Frequency selectivity is a ubiquitous property of auditory neurons. Measuring it in human auditory cortex may be crucial for understanding common auditory deficits, but current non-invasive neuroimaging techniques can only measure the aggregate response of large populations of cells, thereby overestimating tuning width. Here we attempted to estimate neuronal frequency tuning in human auditory cortex using a combination of fMRI-adaptation paradigm at 7T and computational modelling. We measured the BOLD response in the auditory cortex of eleven participants to a high frequency (3.8 kHz) probe presented alone or preceded by adaptors at different frequencies (0.5 to 3.8 kHz). From these data, we derived both the response tuning curves (the BOLD response to adaptors alone as a function of adaptor frequency) and adaptation tuning curves (the degree of response suppression to the probe as a function of adaptor frequency, assumed to reflect neuronal tuning) in primary and secondary auditory cortical areas, delineated in each participant. Results suggested the existence of both frequency-independent and frequency-specific adaptation components, with the latter being more frequency-tuned than response tuning curves. Using a computational model of neuronal adaptation and BOLD non-linearity in topographically-organized cortex, we demonstrate both that the frequency-specific adaptation component overestimates the underlying neuronal frequency tuning and that frequency-specific and frequency-independent adaptation component cannot easily be disentangled from the adaptation tuning curve. By fitting our model directly to the response and adaptation tuning curves, we derive a range of plausible values for neuronal frequency tuning. Our results suggest that fMRI adaptation is suitable for measuring neuronal frequency tuning properties in human auditory cortex, provided population effects and the non-linearity of BOLD response are taken into account.

The influence of non-neural factors on BOLD signal magnitude

To what extent is the size of the blood-oxygen-level-dependent (BOLD) response influenced by factors other than neural activity? In a re-analysis of three neuroimaging datasets, we find large systematic inhomogeneities in the BOLD response magnitude in primary visual cortex (V1): stimulus-evoked BOLD responses, expressed in units of percent signal change, are up to 50% larger along the representation of the horizontal meridian than the vertical meridian. To assess whether this surprising effect can be interpreted as differences in local neural activity, we quantified several factors that potentially contribute to the size of the BOLD response. We find strong relationships between BOLD response magnitude and cortical thickness, cortical curvature, and the presence of large veins. These relationships are consistently found across subjects and suggest that variation in BOLD response magnitudes across cortical locations reflects, in part, differences in anatomy and vascularization. To compensate for these factors, we implement a regression-based correction method and show that after correction, BOLD responses become more homogeneous across V1. The correction reduces the horizontal/vertical difference by about half, indicating that some of the difference is likely not due to neural activity differences. Additionally, we find that while the cerebral sinuses overlap with the vertical meridian representation in V1, they do not explain the observed horizontal/vertical difference. We conclude that interpretation of variation in BOLD response magnitude across cortical locations should consider the influence of the potential confounding factors of cortical thickness, curvature, and vascularization.

Gustatory cortex is involved in evidence accumulation during food choice

Food choice is one of the most fundamental and most frequent value-based decisions for all animals including humans. However, the neural circuitry involved in food-based decisions is only recently being addressed. Given the relatively fast dynamics of decision formation, EEG-informed fMRI analysis is highly beneficial for localizing this circuitry in humans. Here by using the EEG correlates of evidence accumulation in a simultaneously recorded EEG-fMRI dataset, we found a significant role for the right temporal-parietal operculum (PO) and medial insula including gustatory cortex (GC) in binary choice between food items. These activations were uncovered by using the EEG energy (power 2) as the BOLD regressor and were missed if conventional analysis with the EEG signal itself were to be used, in agreement with theoretical predictions for EEG and BOLD relations. No significant positive correlations were found with higher powers of EEG (powers 3 or 4) pointing to specificity and sufficiency of EEG energy as the main correlate of the BOLD response. This finding extends the role of cortical areas traditionally involved in palatability processing to value-based decision making and offers the EEG energy as a key regressor of BOLD response in simultaneous EEG-fMRI designs.

Callous-Unemotional Traits Moderate the Relationship Between Irritability and Threatening Responding

Background: Irritability and callous-unemotional (CU; reduced guilt/empathy) traits vary dimensionally in the typically developing population but may be particularly marked in youth with conduct disorder (CD). While these dimensional traits are positively correlated, they have been associated with divergent forms of dysfunction, particularly with respect to threat processing (i.e., irritability with increased, and CU traits with decreased, threat responsiveness). This suggests that interactions between these two dimensions may be complex at the neurobiological level. However, this issue has received minimal empirical attention.Methods: The study included 105 adolescents (typically developing and cases with CD; N = 59). They were scanned with fMRI during a looming threat task that involved images of threatening and neutral human faces or animals that appeared to be either looming or receding.Results: Significant irritability-by-CU traits-by-Direction-by-Emotion interactions were seen within right thalamus/PAG, left lingual gyrus and right fusiform gyrus; irritability was positively associated with the BOLD response for Looming Threatening vs. Receding Threatening trials, particularly for youth with low CU traits. In contrast, CU traits were negatively associated with the same differential BOLD response but particularly for youth showing higher levels of irritability. Similar findings were seen within left ventral anterior and posterior cingulate cortices, though the addition of the interaction with CU traits was only seen at slightly more lenient thresholds.Conclusions: The results support previous work linking irritability to increased, and CU traits to reduced, threat responsiveness. However, for adolescents with high irritability, if CU traits are also high, the underlying neuropathology appears to relate to reduced, rather than increased, threat responsiveness.

Lactate transporters in the rat barrel cortex sustain whisker-dependent BOLD fMRI signal and behavioral performance

Lactate is an efficient neuronal energy source, even in presence of glucose. However, the importance of lactate shuttling between astrocytes and neurons for brain activation and function remains to be established. For this purpose, metabolic and hemodynamic responses to sensory stimulation have been measured by functional magnetic resonance spectroscopy and blood oxygen level-dependent (BOLD) fMRI after down-regulation of either neuronal MCT2 or astroglial MCT4 in the rat barrel cortex. Results show that the lactate rise in the barrel cortex upon whisker stimulation is abolished when either transporter is down-regulated. Under the same paradigm, the BOLD response is prevented in all MCT2 down-regulated rats, while about half of the MCT4 down-regulated rats exhibited a loss of the BOLD response. Interestingly, MCT4 down-regulated animals showing no BOLD response were rescued by peripheral lactate infusion, while this treatment had no effect on MCT2 down-regulated rats. When animals were tested in a novel object recognition task, MCT2 down-regulated animals were impaired in the textured but not in the visual version of the task. For MCT4 down-regulated animals, while all animal succeeded in the visual task, half of them exhibited a deficit in the textured task, a similar segregation into two groups as observed for BOLD experiments. Our data demonstrate that lactate shuttling between astrocytes and neurons is essential to give rise to both neurometabolic and neurovascular couplings, which form the basis for the detection of brain activation by functional brain imaging techniques. Moreover, our results establish that this metabolic cooperation is required to sustain behavioral performance based on cortical activation.

Cerebral blood flow predicts multiple demand network activity and fluid intelligence across the lifespan

The preservation of cognitive function into old age is a public health priority. Cerebral hypoperfusion is a hallmark of dementia but its impact on maintaining cognitive ability across the lifespan is less clear. We investigated the relationship between baseline cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) response during a fluid reasoning task in a population-based adult lifespan cohort (N=227, age 18-88 years). As age differences in baseline CBF could lead to non-neuronal contributions to the BOLD signal, we introduced commonality analysis to neuroimaging, in order to dissociate performance-related CBF effects from the physiological confounding effects of CBF on the BOLD response. Accounting for CBF, we confirmed that performance- and age-related differences in BOLD responses in the multiple-demand network (MDN) implicated in fluid reasoning. Differences in baseline CBF across the lifespan explained not only performance-related BOLD responses, but also performance-independent BOLD responses. Our results suggest that baseline CBF is important for maintaining cognitive function, while its non-neuronal contributions to BOLD signals reflect an age-related confound. Maintaining perfusion into old age may serve to support brain function with behavioural advantage, regulating brain health.