The neural basis of resting-state fMRI functional connectivity in fronto-limbic circuits revealed by chemogenetic manipulation.

Measures of fMRI resting-state functional connectivity (rs-FC) are an essential tool for basic and clinical investigations of fronto-limbic circuits. Understanding the relationship between rs-FC and the underlying patterns of neural activity in these circuits is therefore vital. Here we introduced inhibitory designer receptors exclusively activated by designer drugs (DREADDs) into the amygdala of two male macaques. We evaluated the causal effect of activating the DREADD receptors on rs-FC and neural activity within circuits connecting amygdala and frontal cortex. Activating the inhibitory DREADD increased rs-FC between amygdala and ventrolateral prefrontal cortex. Neurophysiological recordings revealed that the DREADD-induced increase in fMRI rs-FC was associated with increased local field potential coherency in the alpha band (6.5-14.5 Hz) between amygdala and ventrolateral prefrontal cortex. Thus, our multi-modal approach reveals the specific signature of neuronal activity that underlies rs-FC in fronto-limbic circuits.

Preferences reveal dissociable encoding across prefrontal-limbic circuits.

Individual preferences for the flavor of different foods and fluids exert a strong influence on behavior. Most current theories posit that preferences are integrated with other state variables in the orbitofrontal cortex (OFC), which is thought to derive the relative subjective value of available options to guide choice behavior. Here, we report that instead of a single integrated valuation system in the OFC, another complementary one is centered in the ventrolateral prefrontal cortex (vlPFC) in macaques. Specifically, we found that the OFC and vlPFC preferentially represent outcome flavor and outcome probability, respectively, and that preferences are separately integrated into value representations in these areas. In addition, the vlPFC, but not the OFC, represented the probability of receiving the available outcome flavors separately, with the difference between these representations reflecting the degree of preference for each flavor. Thus, both the vlPFC and OFC exhibit dissociable but complementary representations of subjective value, both of which are necessary for decision-making.

Dissociable representations of decision variables within subdivisions of macaque orbitofrontal and ventrolateral frontal cortex.

Ventral frontal cortex (VFC) in macaques is involved in many affective and cognitive processes and has a key role in flexibly guiding reward-based decision-making. VFC is composed of a set of anatomically distinct subdivisions that are within the orbitofrontal cortex, ventrolateral prefrontal cortex, and anterior insula. In part, because prior studies have lacked the resolution to test for differences, it is unclear if neural representations related to decision-making are dissociable across these subdivisions. Here we recorded the activity of thousands of neurons within eight anatomically defined subregions of VFC in macaque monkeys performing a two-choice probabilistic task for different fruit juices outcomes. We found substantial variation in the encoding of decision variables across these eight subdivisions. Notably, ventrolateral subdivision 12l was unique relative to the other areas that we recorded from as the activity of single neurons integrated multiple attributes when monkeys evaluated the different choice options. Activity within 12o, by contrast, more closely represented reward probability and whether reward was received on a given trial. Orbitofrontal area 11m/l contained more specific representations of the quality of the outcome that could be earned later on. We also found that reward delivery encoding was highly distributed across all VFC subregions, while the properties of the reward, such as its flavor, were more strongly represented in areas 11m/l and 13m. Taken together, our work reveals the diversity of encoding within the various anatomically distinct subdivisions of VFC in primates.

Single basolateral amygdala neurons in macaques exhibit distinct connectional motifs with frontal cortex.

Basolateral amygdala (BLA) projects widely across the macaque frontal cortex, and amygdalo-frontal projections are critical for appropriate emotional responding and decision making. While it is appreciated that single BLA neurons branch and project to multiple areas in frontal cortex, the organization and frequency of this branching has yet to be fully characterized. Here, we determined the projection patterns of more than 3,000 macaque BLA neurons. We found that one-third of BLA neurons had two or more distinct projection targets in frontal cortex and subcortical structures. The patterns of single BLA neuron projections to multiple areas were organized into repeating motifs that targeted distinct sets of areas in medial and ventral frontal cortex, indicative of separable BLA networks. Our findings begin to reveal the rich structure of single-neuron connections in the non-human primate brain, providing a neuroanatomical basis for the role of BLA in coordinating brain-wide responses to valent stimuli.

The neural basis of resting-state fMRI functional connectivity in fronto-limbic circuits revealed by chemogenetic manipulation.

Measures of fMRI resting-state functional connectivity (rs-FC) are an essential tool for basic and clinical investigations of fronto-limbic circuits. Understanding the relationship between rs-FC and neural activity in these circuits is therefore vital. Here we introduced inhibitory designer receptors exclusively activated by designer drugs (DREADDs) into the macaque amygdala and activated them with a highly selective and potent DREADD agonist, deschloroclozapine. We evaluated the causal effect of activating the DREADD receptors on rs-FC and neural activity within circuits connecting amygdala and frontal cortex. Interestingly, activating the inhibitory DREADD increased rs-FC between amygdala and ventrolateral prefrontal cortex. Neurophysiological recordings revealed that the DREADD-induced increase in fMRI rs-FC was associated with increased local field potential coherency in the alpha band (6.5-14.5Hz) between amygdala and ventrolateral prefrontal cortex. Thus, our multi-disciplinary approach reveals the specific signature of neuronal activity that underlies rs-FC in fronto-limbic circuits.

The Differential Weights of Motivational and Task Performance Measures on Medial and Lateral Frontal Neural Activity.

Behavioral adaptations are triggered by different constraints given by rules, and are informed by outcomes, or motivational changes. Neural activity in multiple frontal areas is modulated during behavioral adaptations, but the source of these modulations and the nature of the mechanisms involved are unclear. Here we tested how different variables related to changes in task performance and to behavioral adaptation impact the amplitude of event-related local field potentials (LFPs) in the lateral prefrontal and midcingulate cortex of male rhesus macaques. We found that the behavioral task used induced consistently different types of performance modulation: in relation to task difficulty (imposed by the experimental setup), to successes and errors, and to the time spent in the task. Difficulty had a significant effect on monkeys' accuracy and reaction times. Interestingly, there is also a strong interaction between difficulty and trial success on the reaction times variation. However, LFP modulations were mostly related to reaction times, touch position, feedback valence and time-in-session, with little, if any, effect of difficulty. Hence, difficulty modulated performance but not LFP activity. This suggests that, in our experimental design, execution, regulation, and motivation-related factors are the main factors influencing medial and lateral frontal activity.SIGNIFICANCE STATEMENT Adapting decisions might be determined by several mechanisms and might be driven by motivational factors and/or factors inherent to the task at hand. Multiple frontal areas contribute to behavioral adaptations. One current challenge is to understand which information they process contributes to behavioral changes. Diverging views have emerged on whether task demands, like the decision difficulty, or factors linked to incentives to adapt, are driving frontal activity. Here we show that task difficulty had a strong effect on performance (accuracy and reaction times) but little effect on LFP recorded in monkey lateral prefrontal and midcingulate cortex. However, information related to actions, outcome valence, and time-in-session had major influences. Thus, task difficulty modulated performance but not LFP activity in frontal areas.

Preferences reveal separable valuation systems in prefrontal-limbic circuits.

Individual preferences for the flavor of different foods and fluids exert a strong influence on behavior. Most current theories posit that preferences are integrated with other state variables in orbitofrontal cortex (OFC), which is thought to derive the relative subjective value of available options to drive choice behavior. Here we report that instead of a single integrated valuation system in OFC, another separate one is centered in ventrolateral prefrontal cortex (vlPFC) in macaque monkeys. Specifically, we found that OFC and vlPFC preferentially represent outcome flavor and outcome probability, respectively, and that preferences are separately integrated into these two aspects of subjective valuation. In addition, vlPFC, but not OFC, represented the outcome probability for the two options separately, with the difference between these representations reflecting the degree of preference. Thus, there are at least two separable valuation systems that work in concert to guide choices and that both are biased by preferences.

High-throughput sequencing of macaque basolateral amygdala projections reveals dissociable connectional motifs with frontal cortex.

The basolateral amygdala (BLA) projects widely across the macaque frontal cortex1-4, and amygdalo-frontal projections are critical for optimal emotional responding5 and decision-making6. Yet, little is known about the single-neuron architecture of these projections: namely, whether single BLA neurons project to multiple parts of the frontal cortex. Here, we use MAPseq7 to determine the projection patterns of over 3000 macaque BLA neurons. We found that one-third of BLA neurons have two or more distinct targets in parts of frontal cortex and of subcortical structures. Further, we reveal non-random structure within these branching patterns such that neurons with four targets are more frequently observed than those with two or three, indicative of widespread networks. Consequently, these multi-target single neurons form distinct networks within medial and ventral frontal cortex consistent with their known functions in regulating mood and decision-making. Additionally, we show that branching patterns of single neurons shape functional networks in the brain as assessed by fMRI-based functional connectivity. These results provide a neuroanatomical basis for the role of the BLA in coordinating brain-wide responses to valent stimuli8 and highlight the importance of high-resolution neuroanatomical data for understanding functional networks in the brain.

Comparative basolateral amygdala connectomics reveals dissociable single-neuron projection patterns to frontal cortex in macaques and mice.

The basolateral amygdala (BLA) projects to the frontal cortex (FC) in both rodents and primates, but the comparative organization of single-neuron BLA-FC projections is unknown. Using a barcoded connectomic approach, we found that BLA neurons are more likely to project to multiple distinct parts of FC in mice than in macaques. Further, while single BLA neuron projections to nucleus accumbens are similarly organized in mice and macaques, BLA-FC connections differ.

Inhibitory control of frontal metastability sets the temporal signature of cognition.

Cortical dynamics are organized over multiple anatomical and temporal scales. The mechanistic origin of the temporal organization and its contribution to cognition remain unknown. Here, we demonstrate the cause of this organization by studying a specific temporal signature (time constant and latency) of neural activity. In monkey frontal areas, recorded during flexible decisions, temporal signatures display specific area-dependent ranges, as well as anatomical and cell-type distributions. Moreover, temporal signatures are functionally adapted to behaviourally relevant timescales. Fine-grained biophysical network models, constrained to account for experimentally observed temporal signatures, reveal that after-hyperpolarization potassium and inhibitory GABA-B conductances critically determine areas' specificity. They mechanistically account for temporal signatures by organizing activity into metastable states, with inhibition controlling state stability and transitions. As predicted by models, state durations non-linearly scale with temporal signatures in monkey, matching behavioural timescales. Thus, local inhibitory-controlled metastability constitutes the dynamical core specifying the temporal organization of cognitive functions in frontal areas.

Piecing together the orbitofrontal puzzle.

For almost a century, researchers have puzzled over how the orbitofrontal cortex (OFC) contributes to behavior. Our understanding of the functions of this area has evolved as each new finding and piece of information is added to complete the larger picture. Despite this, the full picture of OFC function is incomplete. Here we begin by reviewing recent (and not so recent) theories of how OFC contributes to behavior. We then go onto highlight emerging work that has helped to broaden perspectives on the role that OFC plays in contingent learning, interoception, and social behavior. How OFC contributes to these aspects of behavior is not well understood. Here we argue that only by establishing where and how these and other functions fit within the puzzle of OFC, either alone or as part of larger brain-wide circuits, will we be able to fully realize the functions of this area. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The Value of Persistent Value.

In this issue of Neuron, Bari et al. (2019) show that neurons in medial frontal cortex, but not a nearby premotor area, encode the relative value of available options with long-lasting persistent activity states during naturalistic foraging. These long-lasting activity states serve to preferentially guide choices to more likely rewarded options.

Linking dynamic patterns of neural activity in orbitofrontal cortex with decision making.

Humans and animals demonstrate extraordinary flexibility in choice behavior, particularly when deciding based on subjective preferences. We evaluate options on different scales, deliberate, and often change our minds. Little is known about the neural mechanisms that underlie these dynamic aspects of decision-making, although neural activity in orbitofrontal cortex (OFC) likely plays a central role. Recent evidence from studies in macaques shows that attention modulates value responses in OFC, and that ensembles of OFC neurons dynamically signal different options during choices. When contexts change, these ensembles flexibly remap to encode the new task. Determining how these dynamic patterns emerge and relate to choices will inform models of decision-making and OFC function.

Prefrontal Markers and Cognitive Performance Are Dissociated during Progressive Dopamine Lesion.

Dopamine is thought to directly influence the neurophysiological mechanisms of both performance monitoring and cognitive control-two processes that are critically linked in the production of adapted behaviour. Changing dopamine levels are also thought to induce cognitive changes in several neurological and psychiatric conditions. But the working model of this system as a whole remains untested. Specifically, although many researchers assume that changing dopamine levels modify neurophysiological mechanisms and their markers in frontal cortex, and that this in turn leads to cognitive changes, this causal chain needs to be verified. Using longitudinal recordings of frontal neurophysiological markers over many months during progressive dopaminergic lesion in non-human primates, we provide data that fail to support a simple interaction between dopamine, frontal function, and cognition. Feedback potentials, which are performance-monitoring signals sometimes thought to drive successful control, ceased to differentiate feedback valence at the end of the lesion, just before clinical motor threshold. In contrast, cognitive control performance and beta oscillatory markers of cognitive control were unimpaired by the lesion. The differing dynamics of these measures throughout a dopamine lesion suggests they are not all driven by dopamine in the same way. These dynamics also demonstrate that a complex non-linear set of mechanisms is engaged in the brain in response to a progressive dopamine lesion. These results question the direct causal chain from dopamine to frontal physiology and on to cognition. They imply that biomarkers of cognitive functions are not directly predictive of dopamine loss.

Specific frontal neural dynamics contribute to decisions to check.

Curiosity and information seeking potently shapes our behaviour and are thought to rely on the frontal cortex. Yet, the frontal regions and neural dynamics that control the drive to check for information remain unknown. Here we trained monkeys in a task where they had the opportunity to gain information about the potential delivery of a large bonus reward or continue with a default instructed decision task. Single-unit recordings in behaving monkeys reveal that decisions to check for additional information first engage midcingulate cortex and then lateral prefrontal cortex. The opposite is true for instructed decisions. Importantly, deciding to check engages neurons also involved in performance monitoring. Further, specific midcingulate activity could be discerned several trials before the monkeys actually choose to check the environment. Our data show that deciding to seek information on the current state of the environment is characterized by specific dynamics of neural activity within the prefrontal cortex.

Midcingulate Motor Map and Feedback Detection: Converging Data from Humans and Monkeys.

The functional and anatomical organization of the cingulate cortex across primate species is the subject of considerable and often confusing debate. The functions attributed to the midcingulate cortex (MCC) embrace, among others, feedback processing, pain, salience, action-reward association, premotor functions, and conflict monitoring. This multiplicity of functional concepts suggests either unresolved separation of functional contributions or integration and convergence. We here provide evidence from recent experiments in humans and from a meta-analysis of monkey data that MCC feedback-related activity is generated in the rostral cingulate premotor area by specific body maps directly related to the modality of feedback. As such, we argue for an embodied mechanism for adaptation and exploration in MCC. We propose arguments and precise tools to resolve the origins of performance monitoring signals in the medial frontal cortex, and to progress on issues regarding homology between human and nonhuman primate cingulate cortex.

The Effects of Cognitive Control and Time on Frontal Beta Oscillations.

Frontal beta oscillations are associated with top-down control mechanisms but also change over time during a task. It is unclear whether change over time represents another control function or a neural instantiation of vigilance decrements over time, the time-on-task effect. We investigated how frontal beta oscillations are modulated by cognitive control and time. We used frontal chronic electrocorticography in monkeys performing a trial-and-error task, comprising search and repetition phases. Specific beta oscillations in the delay period of each trial were modulated by task phase and adaptation to feedback. Beta oscillations in this same period showed a significant within-session change. These separate modulations of beta oscillations did not interact. Crucially, and in contrast to previous investigations, we examined modulations of beta around spontaneous pauses in work. After pauses, the beta power modulation was reset and the cognitive control effect was maintained. Cognitive performance was also maintained whereas behavioral signs of fatigue continued to increase. We propose that these beta oscillations reflect multiple factors contributing to the regulation of cognitive control. Due to the effect of pauses, the time-sensitive factor cannot be a neural correlate of time-on-task but may reflect attentional effort.

Time-frequency characterization of local field potential in a decision making task.

This study seeks to characterize the neuronal mechanisms underlying voluntary decisions to check/verify. In order to describe and potentially decode decisions from brain signals we analyzed intracortical recordings from monkey prefrontal regions obtained during a cognitive task requiring self-initiated as well as cue-instructed decisions. Using local field potentials (LFP) and single units, we analyzed power spectral density, oscillatory modes, power profiles in time, single unit firing rate, and spike-phase relationships in the ß band. Our results point toward specific but variable activation patterns of oscillations in ß band from separate recordings, with task-dependent frequency preference and amplitude modulation of power. The results suggest relationships between particular LFP oscillations and functions engaged at specific time in the task.