From active affordance to active inference: vertical integration of cognition in the cerebral cortex through dual subcortical control systems.

In previous papers, we proposed that the dorsal attention system's top-down control is regulated by the dorsal division of the limbic system, providing a feedforward or impulsive form of control generating expectancies during active inference. In contrast, we proposed that the ventral attention system is regulated by the ventral limbic division, regulating feedback constraints and error-correction for active inference within the neocortical hierarchy. Here, we propose that these forms of cognitive control reflect vertical integration of subcortical arousal control systems that evolved for specific forms of behavior control. The feedforward impetus to action is regulated by phasic arousal, mediated by lemnothalamic projections from the reticular activating system of the lower brainstem, and then elaborated by the hippocampus and dorsal limbic division. In contrast, feedback constraint-based on environmental requirements-is regulated by the tonic activation furnished by collothalamic projections from the midbrain arousal control centers, and then sustained and elaborated by the amygdala, basal ganglia, and ventral limbic division. In an evolutionary-developmental analysis, understanding these differing forms of active affordance-for arousal and motor control within the subcortical vertebrate neuraxis-may help explain the evolution of active inference regulating the cognition of expectancy and error-correction within the mammalian 6-layered neocortex.

Adaptive control of functional connectivity: dorsal and ventral limbic divisions regulate the dorsal and ventral neocortical networks.

The connectional anatomy of the primate cortex is now well-defined by the Structural Model, in which adjacent cortical areas are interconnected in an organized network hierarchy of communication and control. The computational theory of "active inference" can be aligned with this architecture, proposing that predictions descend from higher association areas to be updated by ascending prediction errors from lower (i.e. primary) sensory and motor areas. Given the connectivity, the limbic networks at the apex of the cerebral hierarchy must then be responsible for the most general expectancies, which are propagated through the hierarchy to organize the multiple component network levels of experience and behavior. Anatomical evidence suggests that there are dual limbic divisions, reflecting archicortical (dorsal) and paleocortical (ventral) derivations, resulting in fundamentally different neural mechanisms for managing expectancies across the corticolimbic hierarchy. In the functional connectivity literature, the dorsal attention network is seen to provide top-down or endogenous control of attention, whereas the ventral attention network provides stimulus bound or exogenous attentional control. We review evidence indicating that the dorsal, archicortical division of the limbic system provides a feedforward, impulsive, endogenous mode of motive control, whereas the ventral, paleocortical limbic division provides feedback constraint linked to exogenous events.

Feasibility of a Personal Neuromorphic Emulation.

The representation of intelligence is achieved by patterns of connections among neurons in brains and machines. Brains grow continuously, such that their patterns of connections develop through activity-dependent specification, with the continuing ontogenesis of individual experience. The theory of active inference proposes that the developmental organization of sentient systems reflects general processes of informatic self-evidencing, through the minimization of free energy. We interpret this theory to imply that the mind may be described in information terms that are not dependent on a specific physical substrate. At a certain level of complexity, self-evidencing of living (self-organizing) information systems becomes hierarchical and reentrant, such that effective consciousness emerges as the consequence of a good regulator. We propose that these principles imply that an adequate reconstruction of the computational dynamics of an individual human brain/mind is possible with sufficient neuromorphic computational emulation.

Continuity and change in neural plasticity through embryonic morphogenesis, fetal activity-dependent synaptogenesis, and infant memory consolidation.

There is an apparent continuity in human neural development that can be traced to venerable themes of vertebrate morphogenesis that have shaped the evolution of the reptilian telencephalon (including both primitive three-layered cortex and basal ganglia) and then the subsequent evolution of the mammalian six-layered neocortex. In this theoretical analysis, we propose that an evolutionary-developmental analysis of these general morphogenetic themes can help to explain the embryonic development of the dual divisions of the limbic system that control the dorsal and ventral networks of the human neocortex. These include the archicortical (dorsal limbic) Papez circuits regulated by the hippocampus that organize spatial, contextual memory, as well as the paleocortical (ventral limbic) circuits that organize object memory. We review evidence that these dorsal and ventral limbic divisions are controlled by the differential actions of brainstem lemnothalamic and midbrain collothalamic arousal control systems, respectively, thereby traversing the vertebrate subcortical neuraxis. These dual control systems are first seen shaping the phyletic morphogenesis of the archicortical and paleocortical foundations of the forebrain in embryogenesis. They then provide dual modes of activity-dependent synaptic organization in the active (lemnothalamic) and quiet (collothalamic) stages of fetal sleep. Finally, these regulatory systems mature to form the major systems of memory consolidation of postnatal development, including the rapid eye movement (lemnothalamic) consolidation of implicit memory and social attachment in the first year, and then-in a subsequent stage-the non-REM (collothalamic) consolidation of explicit memory that is integral to the autonomy and individuation of the second year of life.

Neurophysiological mechanisms of implicit and explicit memory in the process of consciousness.

Neurophysiological mechanisms are increasingly understood to constitute the foundations of human conscious experience. These include the capacity for ongoing memory, achieved through a hierarchy of reentrant cross-laminar connections across limbic, heteromodal, unimodal, and primary cortices. The neurophysiological mechanisms of consciousness also include the capacity for volitional direction of attention to the ongoing cognitive process, through a reentrant fronto-thalamo-cortical network regulation of the inhibitory thalamic reticular nucleus. More elusive is the way that discrete objects of subjective experience, such as the color of deep blue or the sound of middle C, could be generated by neural mechanisms. Explaining such ineffable qualities of subjective experience is what Chalmers has called "the hard problem of consciousness," which has divided modern neuroscientists and philosophers alike. We propose that insight into the appearance of the hard problem can be gained through integrating classical phenomenological studies of experience with recent progress in the differential neurophysiology of consolidating explicit versus implicit memory. Although the achievement of consciousness, once it is reflected upon, becomes explicit, the underlying process of generating consciousness, through neurophysiological mechanisms, is largely implicit. Studying the neurophysiological mechanisms of adaptive implicit memory, including brain stem, limbic, and thalamic regulation of neocortical representations, may lead to a more extended phenomenological understanding of both the neurophysiological process and the subjective experience of consciousness.NEW & NOTEWORTHY The process of consciousness, generating the qualia that may appear to be irreducible qualities of experience, can be understood to arise from neurophysiological mechanisms of memory. Implicit memory, organized by the lemnothalamic brain stem projections and dorsal limbic consolidation in REM sleep, supports the unconscious field and the quasi-conscious fringe of current awareness. Explicit memory, organized by the collothalamic midbrain projections and ventral limbic consolidation of NREM sleep, supports the focal objects of consciousness.

Critical periods for the neurodevelopmental processes of externalizing and internalizing.

Research on neurobiological development is providing insight into the nature and mechanisms of human neural plasticity. These mechanisms appear to support two different forms of developmental learning. One form of learning could be described as externalizing, in which neural representations are highly responsive to environmental influences, as the child typically operates under a mode of hedonic approach. A second form of learning supports internalizing, in which motive control separates attention and self-regulation from the immediate influences of the context, particularly when the child faces conditions of avoidance and threat. The dorsal cortical networks of externalizing are organized around dorsal limbic (cingulate, septal, lateral hypothalamic, hippocampal, and ventral striatal) circuits. In contrast, the ventral cortical networks of internalizing are organized around ventral limbic (anterior temporal and orbital cortex, extended amygdala, dorsal striatal, and mediodorsal thalamic) circuits. These dual divisions of the limbic system in turn self-regulate their arousal levels through different brain stem and forebrain neuromodulator projection systems, with dorsal corticolimbic networks regulated strongly by locus coeruleus norepinephrine and brain stem raphe nucleus serotonin projection systems, and ventral corticolimbic networks regulated by ventral tegmental dopamine and forebrain acetylcholine projections. Because the arousal control systems appear to regulate specific properties of neural plasticity in development, an analysis of these systems explains differences between externalizing and internalizing at multiple levels of neural and psychological self-regulation. In neuroscience, the concept of critical periods has been applied to times when experience is essential for the maturation of sensory systems. In a more general neuropsychological analysis, certain periods of the child's development require successful self-regulation through the differential capacities for externalizing and internalizing.

Motive control of unconscious inference: The limbic base of adaptive Bayes.

Current computational models of neocortical processing, described as predictive coding theory, are providing new ways of understanding Helmholtz's classical insight that perception cannot proceed in a data-driven fashion, but instead requires unconscious inference based on prior experience. Predictive coding is a Bayesian process, in which the operations at each lower level of the cortical hierarchy are predicted by prior projections of expectancies from a higher level, and are then updated by error-correction with lower level evidence. To generalize the predictive coding model to the human neocortex as a whole requires aligning the Bayesian negotiation of prior expectancies with sensory and motor evidence not only within the connectional architecture of the neocortex (primary sensory/motor, unimodal association areas, and heteromodal association areas) but also with the limbic cortex that forms the base for the adaptive control of the heteromodal areas and thereby the cerebral hemisphere as a whole. By reviewing the current evidence on the anatomy of the human corticolimbic connectivity (now formalized as the Structural Model) we address the problem of how limbic cortex resonates to the homeostatic, personal significance of events to provide Bayesian priors to organize the operations of predictive coding across the multiple levels of the neocortex. By reviewing both classical evidence and current models of control exerted between limbic and neocortical networks, we suggest a neuropsychological theory of human cognition, the adaptive Bayes process model, in which prior expectancies are not simply rationalized propositions, but rather affectively-charged expectancies that bias the interpretation of sensory data and action affordances to support allostasis, the motive control of expectancies for future events.

Transcranial Electrical Stimulation targeting limbic cortex increases the duration of human deep sleep.

BACKGROUND: Researchers have proposed that impaired sleep may be a causal link in the progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD). Several recent findings suggest that enhancing deep sleep (N3) may improve neurological health in persons with MCI, and buffer the risk for AD. Specifically, Transcranial Electrical Stimulation (TES) of frontal brain areas, the inferred source of the Slow Oscillations (SOs) of N3 sleep, can extend N3 sleep duration and improve declarative memory for recently learned information. Recent work in our laboratory using dense array Electroencephalography (dEEG) localized the sources of SOs to anterior limbic sites - suggesting that targeting these sites with TES may be more effective for enhancing N3. METHODS: For the present study, we recruited 13 healthy adults (M = 42 years) to participate in three all-night sleep EEG recordings where they received low level (0.5 mA) TES designed to target anterior limbic areas and a sham stimulation (placebo). We used a convolutional neural network, trained and tested on professionally scored EEG sleep staging, to predict sleep stages for each recording. RESULTS: When compared to the sham session, limbic-targeted TES significantly increased the duration of N3 sleep. TES also significantly increased spectral power in the 0.5-1 Hz frequency band (relative to pre-TES epochs) in left temporoparietal and left occipital scalp regions compared to sham. CONCLUSION: These results suggest that even low-level TES, when specifically targeting anterior limbic sites, can increase deep (N3) sleep and thereby contribute to healthy sleep quality.

Focal limbic sources create the large slow oscillations of the EEG in human deep sleep.

BACKGROUND: Initial observations with the human electroencephalogram (EEG) have interpreted slow oscillations (SOs) of the EEG during deep sleep (N3) as reflecting widespread surface-negative traveling waves that originate in frontal regions and propagate across the neocortex. However, mapping SOs with a high-density array shows the simultaneous appearance of posterior positive voltage fields in the EEG at the time of the frontal-negative fields, with the typical inversion point (apparent source) around the temporal lobe. METHODS: Overnight 256-channel EEG recordings were gathered from 10 healthy young adults. Individual head conductivity models were created using each participant's own structural MRI. Source localization of SOs during N3 was then performed. RESULTS: Electrical source localization models confirmed that these large waves were created by focal discharges within the ventral limbic cortex, including medial temporal and caudal orbitofrontal cortex. CONCLUSIONS: Although the functional neurophysiology of deep sleep involves interactions between limbic and neocortical networks, the large EEG deflections of deep sleep are not created by distributed traveling waves in lateral neocortex but instead by relatively focal limbic discharges.

Evidence that juvenile myoclonic epilepsy is a disorder of frontotemporal corticothalamic networks.

The purpose of this study is to determine regions of cerebral cortex activated during the onset and propagation of dense array electroencephalographic (dEEG) epileptiform discharges in patients with juvenile myoclonic epilepsy (JME), through the use of 256 channel, dense array scalp EEG recordings. Ten patients (16-58 years old) with the clinical diagnosis of JME comprised the study group. In all cases the MRI and neurological exams were normal, while standard EEG recordings documented typical "generalized" 4-6 Hz epileptiform patterns. Outpatient dEEG recordings captured epileptiform discharges in each patient. Localization of onset and spread of discharges in relation to a standard MRI model was accomplished by applying dipole fits and a distributed linear inverse method of cortically constrained source analysis. All patients showed epileptiform discharges that localized to sources that included orbitofrontal/medial frontopolar cortex, while basal-medial temporal lobe sources were observed in 5/10 subjects. In many ways similar to discharges of typical absence, epileptiform patterns in JME are usually irregular and frequently include temporal lobe structures as the dominant contributors to the discharges. We find that epileptiform discharges in patients with JME are not "generalized" in the sense of bilaterally synchronous diffuse onset. Rather, discharges have both localized onsets and a restricted cortical network during propagation that includes regions of frontal and temporal cortex.

Frontolimbic activity in a frustrating task: covariation between patterns of coping and individual differences in externalizing and internalizing symptoms.

Many problem behaviors in youth have been attributed to maladaptive self-regulation in response to frustration. Frontolimbic networks that promote flexible as well as over- and undercontrolled regulation could provide evidence linking cortical mechanisms of self-regulation to the development of internalizing or externalizing symptomology. Specifically, ineffective dorsally mediated inhibitory control may be associated with rule-breaking and substance use behaviors, whereas overengagement of ventral limbic systems responsible for self-monitoring of errors may increase risk of developing anxious and depressed symptomology. In this study, a sample of 9- to 13-year-old children were presented with an emotional go/no-go task. Event-related potentials were used to identify differences in cortical mechanisms related to inhibitory control (indexed with the stimulus-locked medial frontal negativity) and self-monitoring (indexed with the error-related negativity). These measurements were then related to externalizing and internalizing behaviors. As predicted, externalizing problems were associated with smaller medial frontal negativity amplitudes, which indicate undercontrolled self-regulation and poor dorsal mediation of actions. Internalizing symptoms were related to larger error-related negativity amplitudes, demonstrating overregulation and overengagement of ventral limbic systems. These findings suggest that the use of event-related potential methodology with paradigms that elicit cognition-emotion can provide insight into the neural mechanisms of regulatory deficits that result in problem behaviors in youth.

Serotonin: modulator of a drive to withdraw.

Serotonin is a fundamental neuromodulator in both vertebrate and invertebrate nervous systems, with a suspected role in many human mental disorders. Yet, because of the complexity of serotonergic function, researchers have been unable to agree on a general theory. One function suggested for serotonin systems is the avoidance of threat. We propose and review evidence for an alternative hypothesis, that a phylogenetically primitive of function of serotonin is to oppose the activating neuromodulators (particularly noradrenalin and dopamine). The functional effect of this opposition can be seen as applying a drive to withdraw from dangerous, aversive or high stimulation environments. Proposing that serotonin is involved in a drive to withdraw and seek contentment, instead of a drive to avoid, may be compatible with several lines of evidence on serotonin function and may facilitate a better understanding of serotonergic neuromodulation in human psychopathology.

Safety of slow-pulsed transcranial electrical stimulation in acute spike suppression.

We examined the effects of slow-pulsed transcranial electrical stimulation (TES) in suppressing epileptiform discharges in seven adults with refractory epilepsy. An MRI-based realistic head model was constructed for each subject and co-registered with 256-channel dense EEG (dEEG). Interictal spikes were localized, and TES targeted the cortical source of each subject's principal spike population. Targeted spikes were suppressed in five subject's (29/35 treatment days overall), and nontargeted spikes were suppressed in four subjects. Epileptiform activity did not worsen. This study suggests that this protocol, designed to induce long-term depression (LTD), is safe and effective in acute suppression of interictal epileptiform discharges.

A single-trial analytic framework for EEG analysis and its application to target detection and classification.

Modern neuroimaging technologies afford a non-invasive view into the functions of the human brain with great spatial (fMRI) and temporal resolution (EEG). However, common signal analytic methods require averaging over many trials, which limits the potential for practical application of these technologies. In this paper we advance a novel single-trial analysis method for EEG and demonstrate this approach with a target detection task. The method utilizes a framework consisting of multiple processing modules that can be applied in whole or in part, including noise mitigation, source-space transformation, discriminant analysis, and performance evaluation. The framework introduces an enhanced noise mitigation technology based on Directed Components Analysis (DCA) that improves upon existing spatial filtering techniques. Source-space transformation, utilizing a finite difference model (FDM) of the human head, estimates activity measures of the cortical sources involved in task performance. Such a source-space discrimination provides measurement invariance between training and testing sessions and holds the promise of providing a degree of classification not possible with scalp-recorded EEG. The framework's discrimination modules interface with performance evaluation modules to generate classification performance statistics. When applied to EEG acquired during performance of a target detection task, this method demonstrated that neural signatures of target recognition correctly classified up to 87% of targets in a rapid serial visual presentation (RSVP) of target/non-target images. On average, the single-trial classification method resulted in greater than 60% improvement over behavioral performance for target detection.

Localization of extratemporal seizure with noninvasive dense-array EEG. Comparison with intracranial recordings.

A 13-year-old girl presented with refractory seizures since the age of 5 years. Clinical exam and MRI studies were normal. Ictal EEG discharges suggested possible left posterior quadrant distribution but were not well localized with standard methods. A seizure was recorded during 128-channel EEG video long-term monitoring prior to invasive recordings. Applying a source analysis method, seizure onset and propagation patterns were calculated and displayed on an MRI model. The onset was localized to the left inferior posterior occipital cortex, followed by propagation to the right, then left, posterior cerebral hemispheres, and finally to the left superior-medial parietal lobe. These patterns were replicated closely on subsequent invasive recordings. Surgery was based on intracranial findings and she is seizure-free 30 months after resection. Noninvasive dense-array EEG, used in conjunction with realistic source analysis methods, may have the potential to assist in localizing seizure onsets when standard methods fail.

EEG source imaging of epileptic activity at seizure onset.

Surgical resection of the seizure onset zone (SOZ) requires that this region of the cortex is accurately localized. The onset of a seizure may be marked by transient discharges, but it also may be accompanied by oscillatory, sinusoidal electrographic activity, such as the EEG theta rhythm. However, because of the superposition of the seizure signal with other electrical signals, including noise artifacts and non-seizure brain activity, noninvasive Electrical Source Imaging (ESI) of the ictal EEG activity at seizure onset remains a challenging task for surgical planning. In the present study, we localize the SOZ from oscillatory features of the EEG at the ictal onset using 256-channel high density electroencephalography (HD-EEG), exact sensor positions, and individual electrical head models constructed from the patient's T1 magnetic resonance image (MRI). Epileptic activities at the seizure onset were characterized with joint time-frequency analysis and source estimated by standardized low resolution electromagnetic tomography (sLORETA) inverse method. The consistency of this localization was examined across multiple seizures for individual patients. For validation, results were compared to three clinical criteria: (1) epileptogenic lesions, (2) seizure onset observed in intracranial EEG, and (3) successful surgical outcomes. In this set of 84 seizures, the onsets of 56 seizures could be localized. For the lateralization measure, the results from HD-EEG with interictal spikes (8/10) and with ictal onset (10/10) were more accurate than international 10-20 EEG for interictal spikes (5/10) and ictal onset (5/10). ESI from HD-EEG with ictal onset (9/10) had greater concordance to the clinical criteria than HD-EEG with interictal spikes (6/10). Noninvasive ESI of oscillatory features at ictal onset using 256-channel HD-EEG and high-resolution individual head models can make a useful contribution to the clinical localization of the SOZ in presurgical planning.

Neural mechanisms for learning actions in context.

The transition from actions that require effortful attention to those that are exercised automatically reflects the progression of learning. Full automaticity marks the performance of the expert. Research on changes in brain activity from novice to skilled performance has been consistent with this behavioral characterization, showing that a highly practiced skill often requires less brain activation than before practice. Moreover, the decrease in brain activity with practice is most pronounced in the general or executive control processes mediated by frontal lobe networks. Consistent with these human cognitive neuroscience findings, animal neurophysiological evidence suggests that two elementary learning systems support different stages of skill acquisition. One system supports rapid and focused acquisition of new skills in relation to threats and violations of expectancies. The other involves a gradual process of updating a configural model of the environmental context. We collected dense array electroencephalography as participants performed an arbitrary associative ("code learning") task. We predicted that frontal lobe activity would decrease, whereas posterior cortical activity would increase, as the person gains the knowledge required for appropriate action. Both predictions were confirmed. In addition, we found that learning resulted in an unexpected increase in activity in the medial frontal lobe (the medial frontal negativity or MFN). Although preliminary, these findings suggest that the specific mechanisms of learning in animal neurophysiology studies may prove informative for understanding the neural basis of human learning and executive cognitive control.

Dynamic Responses in Brain Networks to Social Feedback: A Dual EEG Acquisition Study in Adolescent Couples.

Adolescence is a sensitive period for the development of romantic relationships. During this period the maturation of frontolimbic networks is particularly important for the capacity to regulate emotional experiences. In previous research, both functional magnetic resonance imaging (fMRI) and dense array electroencephalography (dEEG) measures have suggested that responses in limbic regions are enhanced in adolescents experiencing social rejection. In the present research, we examined social acceptance and rejection from romantic partners as they engaged in a Chatroom Interact Task. Dual 128-channel dEEG systems were used to record neural responses to acceptance and rejection from both adolescent romantic partners and unfamiliar peers (N = 75). We employed a two-step temporal principal component analysis (PCA) and spatial independent component analysis (ICA) approach to statistically identify the neural components related to social feedback. Results revealed that the early (288 ms) discrimination between acceptance and rejection reflected by the P3a component was significant for the romantic partner but not the unfamiliar peer. In contrast, the later (364 ms) P3b component discriminated between acceptance and rejection for both partners and peers. The two-step approach (PCA then ICA) was better able than either PCA or ICA alone in separating these components of the brain's electrical activity that reflected both temporal and spatial phases of the brain's processing of social feedback.

Principal components of electrocortical activity during self-evaluation indicate depressive symptom severity.

Negative self-evaluation is an important psychological characteristic of depression. In order to study the underlying neural mechanisms, we examined event-related potentials (ERPs) during a self-evaluation task in a community sample (N = 150) of adults reporting a range of depressive symptoms. Principal components analysis (PCA) was used to separate processes that overlap in the average ERP, and neural source analysis was applied to localize the ERP components, with a particular focus on the frontal networks that are thought to be critical to affective self-regulation in depression. Consistent with previous research, individuals reporting greater depression showed enhanced negativity over medial frontal regions as well as attenuation of the late positive potential over parietal regions. Examining loadings of frontal sources on the ERP components showed that activity in the right inferior frontal region may be particularly important for depressed individuals: activity in this region declined as symptoms became more severe. Characterizing brain mechanisms of self-evaluation on the timescale of cognitive events may provide insight into the neural mechanisms of self-regulation that are important in cognitive therapy, and that could be made more amenable to change through increasing neuroplasticity with targeted non-invasive neuromodulation.