Attention-dependent modulation of cortical taste circuits revealed by granger causality with signal-dependent noise

We show, for the first time, that in cortical areas, for example the insular, orbitofrontal, and lateral prefrontal cortex, there is signal-dependent noise in the fMRI blood-oxygen level dependent (BOLD) time series, with the variance of the noise increasing approximately linearly with the square of the signal. Classical Granger causal models are based on autoregressive models with time invariant covariance structure, and thus do not take this signal-dependent noise into account. To address this limitation, here we describe a Granger causal model with signal-dependent noise, and a novel, likelihood ratio test for causal inferences. We apply this approach to the data from an fMRI study to investigate the source of the top-down attentional control of taste intensity and taste pleasantness processing. The Granger causality with signal-dependent noise analysis reveals effects not identified by classical Granger causal analysis. In particular, there is a top-down effect from the posterior lateral prefrontal cortex to the insular taste cortex during attention to intensity but not to pleasantness, and there is a top-down effect from the anterior and posterior lateral prefrontal cortex to the orbitofrontal cortex during attention to pleasantness but not to intensity. In addition, there is stronger forward effective connectivity from the insular taste cortex to the orbitofrontal cortex during attention to pleasantness than during attention to intensity. These findings indicate the importance of explicitly modeling signal-dependent noise in functional neuroimaging, and reveal some of the processes involved in a biased activation theory of selective attention

The Functional Architecture of the Brain Underlies Strategic Deception in Impression Management

Impression management, as one of the most essential skills of social function, impacts one’s survival and success in human societies. However, the neural architecture underpinning this social skill remains poorly understood. By employing a two-person bargaining game, we exposed three strategies involving distinct cognitive processes for social impression management with different levels of strategic deception. We utilized a novel adaptation of Granger causality accounting for signal-dependent noise (SDN), which captured the directional connectivity underlying the impression management during the bargaining game. We found that the sophisticated strategists engaged stronger directional connectivity from both dorsal anterior cingulate cortex and retrosplenial cortex to rostral prefrontal cortex, and the strengths of these directional influences were associated with higher level of deception during the game. Using the directional connectivity as a neural signature, we identified the strategic deception with 80% accuracy by a machine-learning classifier. These results suggest that different social strategies are supported by distinct patterns of directional connectivity among key brain regions for social cognition

Altered structural and effective connectivity in anorexia and bulimia nervosa in circuits that regulate energy and reward homeostasis.

Anorexia and bulimia nervosa are severe eating disorders that share many behaviors. Structural and functional brain circuits could provide biological links that those disorders have in common. We recruited 77 young adult women, 26 healthy controls, 26 women with anorexia and 25 women with bulimia nervosa. Probabilistic tractography was used to map white matter connectivity strength across taste and food intake regulating brain circuits. An independent multisample greedy equivalence search algorithm tested effective connectivity between those regions during sucrose tasting. Anorexia and bulimia nervosa had greater structural connectivity in pathways between insula, orbitofrontal cortex and ventral striatum, but lower connectivity from orbitofrontal cortex and amygdala to the hypothalamus (P<0.05, corrected for comorbidity, medication and multiple comparisons). Functionally, in controls the hypothalamus drove ventral striatal activity, but in anorexia and bulimia nervosa effective connectivity was directed from anterior cingulate via ventral striatum to the hypothalamus. Across all groups, sweetness perception was predicted by connectivity strength in pathways connecting to the middle orbitofrontal cortex. This study provides evidence that white matter structural as well as effective connectivity within the energy-homeostasis and food reward-regulating circuitry is fundamentally different in anorexia and bulimia nervosa compared with that in controls. In eating disorders, anterior cingulate cognitive-emotional top down control could affect food reward and eating drive, override hypothalamic inputs to the ventral striatum and enable prolonged food restriction

Feed-Forward Propagation of Temporal and Rate Information between Cortical Populations during Coherent Activation in Engineered In Vitro Networks.

Transient propagation of information across neuronal assembles is thought to underlie many cognitive processes. However, the nature of the neural code that is embedded within these transmissions remains uncertain. Much of our understanding of how information is transmitted among these assemblies has been derived from computational models. While these models have been instrumental in understanding these processes they often make simplifying assumptions about the biophysical properties of neurons that may influence the nature and properties expressed. To address this issue we created an in vitro analog of a feed-forward network composed of two small populations (also referred to as assemblies or layers) of living dissociated rat cortical neurons. The populations were separated by, and communicated through, a microelectromechanical systems (MEMS) device containing a strip of microscale tunnels. Delayed culturing of one population in the first layer followed by the second a few days later induced the unidirectional growth of axons through the microtunnels resulting in a primarily feed-forward communication between these two small neural populations. In this study we systematically manipulated the number of tunnels that connected each layer and hence, the number of axons providing communication between those populations. We then assess the effect of reducing the number of tunnels has upon the properties of between-layer communication capacity and fidelity of neural transmission among spike trains transmitted across and within layers. We show evidence based on Victor-Purpura's and van Rossum's spike train similarity metrics supporting the presence of both rate and temporal information embedded within these transmissions whose fidelity increased during communication both between and within layers when the number of tunnels are increased. We also provide evidence reinforcing the role of synchronized activity upon transmission fidelity during the spontaneous synchronized network burst events that propagated between layers and highlight the potential applications of these MEMs devices as a tool for further investigation of structure and functional dynamics among neural populations

Novel measure of olfactory bulb function in health and disease

Present neuroimaging techniques are capable of recording the neural activity from all over the brain but the olfactory bulb (OB). The OB is the first olfactory processing stage of the central nervous system and the site of insult in several neurological disorders, particularly Parkinson’s disease (PD). It has been suggested that the OB has a pivotal role in the olfactory system anal-ogous to primary visual cortex (V1) and thalamus in the visual system. However, due to the existing technical limitations, there has not been any non-invasive technique that can reliably measure the OB function in humans, consequently limiting its functional recording to one in-tracranial study dating back to the 60s. Initially in Study I, a non-invasive method of measuring the function of human OB is devel-oped, so-called electrobulbogram (EBG). In line with previous animal literature as well as the only intracranial study in human OB, it was demonstrated that gamma oscillations on the EBG electrodes occurred shortly after the odor onset. Subsequently, applying source recon-struction analysis provided evidence that observed oscillations were localized to the OB. Ad-ditionally, the OB recording with the EBG method showed a test-retest reliability comparable with visual event related potentials. Notably, the detected gamma oscillations were demon-strated to be insensitive to habituation, the OB’s marked characteristic which has previously been demonstrated in rodents. Last, but not least, assessing the EBG response in an individual who did not have the bilateral OB indicated that the lack of OB results in disappearance of gamma oscillations in the EBG electrodes. Given that Study I determined the possibility of reliably measuring the function of the OB using the EBG, in Study II, I assessed the functional role of OB’s oscillations in the pro-cessing of the odor valence. Odor valence has been suggested to be linked to approach–avoidance responses and therefore, processing of odor valence is thought to be one of the core aspects of odor processing in the olfactory system. Consequently, using combined EBG and EEG recording, OB activity was reconstructed on the source level during processing of odors with different valences. Gamma and beta oscillations were found to be related to va-lence perception in the human OB. Moreover, the early beta oscillations were associated with negative but not positive odors, where these beta oscillations can be linked to preparatory neural responses in the motor cortex. Subsequently, in a separate experiment, negative odors were demonstrated to trigger a whole-body motor avoidance response in the time window overlapping with the valence processes in the OB. These negative odor-elicited motor re-sponses were measured by a force plate as a leaning backward motion. Altogether, the results from Study II indicated that the human OB processes odor valence sequentially in the gamma and beta frequency bands, where the early processing of negative odors in the OB might be facilitating rapid approach-avoidance behaviors. To further evaluate the functional role of the OB in odor processing, in Study III, OB’s communication with its immediate recipient, namely piriform cortex (PC), was assessed. These two areas are critical nodes of the olfactory system which communicate with each other through neural oscillations. The activity of the OB and the PC were reconstructed using a combination of EBG, EEG, and source reconstruction techniques. Subsequently, the cross spectrogram of the OB and the PC was assessed as a measure of functional connectivity where temporal evolution from fast to slow oscillations in the OB–PC connectivity was found during the one second odor processing. Furthermore, the spectrally resolved Granger causal-ity analysis suggested that the afferent connection form the OB to the PC occurred in the gamma and beta bands whereas the efferent connection from the PC to the OB was concen-trated in the theta and delta bands. Notably, odor identity could be deciphered from the low gamma oscillatory pattern in the OB–PC connectivity as early as 100ms after the odor onset. Hence, findings from this study elucidate on our understanding of the bidirectional infor-mation flow in the human olfactory system. Olfactory dysfunction, due to neurodegeneration in the OB, commonly appears several years earlier than the occurrence of the PD-related characteristic motor symptoms. Consequently, a functional measure of the OB may serve as a potential early biomarker of PD. In Study IV, OB function was assessed in PD to answer whether the EBG method can be used to dissociate individuals with a PD diagnosis from healthy age-matched controls. The spectrogram of the EBG signals indicated that there were different values in gamma, beta, and theta for PDs compared with healthy controls. Specifically, six components were found in the EBG re-sponse during early and late time points which together dissociate PDs from controls with a 90% sensitivity and a 100% specificity. Furthermore, these components were linked to med-ication, disease duration and severity, as well as clinical odor identification performance. Overall, these findings support the notion that EBG has a diagnostic value and can be further developed to serve as an early biomarker for PD. In the last study, Study V, the prevalence of COVID-19 was determined using odor intensity ratings as an indication of olfactory dysfunction. Using a large sample data (n = 2440) from a Swedish population, odor intensity ratings of common household items over time were found to be closely associated with prevalence prediction of COVID-19 in the Stockholm region over the same time-period (r = -.83). Impairment in odor intensity rating was further correlated with the number of reported COVID-19 symptoms. Relatedly, individuals who progressed from having no symptoms to having at least one symptom had a marked decline in their odor intensity ratings. The results from this study, given the relatively large sample size, provided a concrete basis for the future studies to further assess the potential association between the deficits in the OB function and olfactory dysfunction in COVID-19. In conclusion, our proposed method for non-invasive measurement of the OB function was shown to provide a reliable recording with a potential as a diagnostic tool for PD. Combining EBG and EEG allowed for reconstruction of the OB signal at the source level, where specific oscillations were found to be critical for odor valence processing and rapid avoidance re-sponse. Moreover, oscillations in different frequency bands were found to be critical for the OB reciprocal communications and transfer of odor identity information to higher order ol-factory subsystems. Finally, COVID-19 was found to be associated with a decline in olfactory acuity which might originate from damage to the patient’s OB. In conclusion, the results from the studies within this thesis provide a new perspective on the functional role of oscillations in the human OB

Dynamic Construction of Stimulus Values in the Ventromedial Prefrontal Cortex

Signals representing the value assigned to stimuli at the time of choice have been repeatedly observed in ventromedial prefrontal cortex (vmPFC). Yet it remains unknown how these value representations are computed from sensory and memory representations in more posterior brain regions. We used electroencephalography (EEG) while subjects evaluated appetitive and aversive food items to study how event-related responses modulated by stimulus value evolve over time. We found that value-related activity shifted from posterior to anterior, and from parietal to central to frontal sensors, across three major time windows after stimulus onset: 150–250 ms, 400–550 ms, and 700–800 ms. Exploratory localization of the EEG signal revealed a shifting network of activity moving from sensory and memory structures to areas associated with value coding, with stimulus value activity localized to vmPFC only from 400 ms onwards. Consistent with these results, functional connectivity analyses also showed a causal flow of information from temporal cortex to vmPFC. Thus, although value signals are present as early as 150 ms after stimulus onset, the value signals in vmPFC appear relatively late in the choice process, and seem to reflect the integration of incoming information from sensory and memory related regions

Using real-time fMRI to influence effective connectivity in the developing emotion regulation network

For most people, adolescence is synonymous with emotional turmoil and it has been shown that early difficulties with emotion regulation can lead to persistent problems for some people. This suggests that intervention during development might reduce long-term negative consequences for those individuals. Recent research has highlighted the suitability of real-time fMRI-based neurofeedback (NF) in training emotion regulation (ER) networks in adults. However, its usefulness in directly influencing plasticity in the maturing ER networks remains unclear. Here, we used NF to teach a group of 17 7–16 year-olds to up-regulate the bilateral insula, a key ER region. We found that all participants learned to increase activation during the up-regulation trials in comparison to the down-regulation trials. Importantly, a subsequent Granger causality analysis of Granger information flow within the wider ER network found that during up-regulation trials, bottom-up driven Granger information flow increased from the amygdala to the bilateral insula and from the left insula to the mid-cingulate cortex, supplementary motor area and the inferior parietal lobe. This was reversed during the down-regulation trials, where we observed an increase in top-down driven Granger information flow to the bilateral insula from mid-cingulate cortex, pre-central gyrus and inferior parietal lobule. This suggests that: 1) NF training had a differential effect on up-regulation vs down-regulation network connections, and that 2) our training was not only superficially concentrated on surface effects but also relevant with regards to the underlying neurocognitive bases. Together these findings highlight the feasibility of using NF in children and adolescents and its possible use for shaping key social cognitive networks during development

A non-reward attractor theory of depression

A non-reward attractor theory of depression is proposed based on the operation of the lateral orbitofrontal cortex and supracallosal cingulate cortex. The orbitofrontal cortex contains error neurons that respond to non-reward for many seconds in an attractor state that maintains a memory of the non-reward. The human lateral orbitofrontal cortex is activated by non-reward during reward reversal, and by a signal to stop a response that is now incorrect. Damage to the human orbitofrontal cortex impairs reward reversal learning. Not receiving reward can produce depression. The theory proposed is that in depression, this lateral orbitofrontal cortex non-reward system is more easily triggered, and maintains its attractor-related firing for longer. This triggers negative cognitive states, which in turn have positive feedback top-down effects on the orbitofrontal cortex non-reward system. Treatments for depression, including ketamine, may act in part by quashing this attractor. The mania of bipolar disorder is hypothesized to be associated with oversensitivity and overactivity in the reciprocally related reward system in the medial orbitofrontal cortex and pregenual cingulate cortex