Frontal Cortical Networks Research Articles

Distributed feedforward and feedback cortical processing supports human speech production.

Speech production is a complex human function requiring continuous feedforward commands together with reafferent feedback processing. These processes are carried out by distinct frontal and temporal cortical networks, but the degree and timing of their recruitment and dynamics remain poorly understood. We present a deep learning architecture that translates neural signals recorded directly from the cortex to an interpretable representational space that can reconstruct speech. We leverage learned decoding networks to disentangle feedforward vs. feedback processing. Unlike prevailing models, we find a mixed cortical architecture in which frontal and temporal networks each process both feedforward and feedback information in tandem. We elucidate the timing of feedforward and feedback-related processing by quantifying the derived receptive fields. Our approach provides evidence for a surprisingly mixed cortical architecture of speech circuitry together with decoding advances that have important implications for neural prosthetics.

Intrinsic brain functional connectivity patterns in alcohol use disorder.

Alcohol use disorder is associated with damaging effects to the brain. This study aimed to examine differences in static and dynamic intrinsic functional connectivity patterns in individuals with a history of alcohol use disorder in comparison to those with no history of alcohol abuse. A total of 55 participants consisting of 23 patients and 32 control individuals underwent neuropsychological assessments and resting-state functional magnetic resonance imaging on a 3 Tesla MRI scanner. Differences in functional connectivity between the two groups were determined using static and dynamic independent component analysis. Differences in static functional connectivity between the two groups were identified in the default mode network, attention network, frontoparietal network, frontal cortical network and cerebellar network. Furthermore, the analyses revealed specific differences in the dynamic temporal characteristics of functional connectivity between the two groups of participants, in a cluster involving key regions in reward, sensorimotor and frontal cortical functional networks, with some connections correlating with the length of sobriety and some others with the severity of drinking. The findings altogether suggest dysregulation in the intrinsic connectivity of cortico-basal ganglia-thalamo-cortical loops that may reflect persistent alcohol use disorder-related network abnormalities, compensatory recovery-related processes whereby additional neural resources are recruited to achieve normal levels of performance, or a predisposition toward developing alcohol use disorder.

Sex influences the brain functional connectivity correlates of originality

Creative cognition is thought to involve two processes, the creation of new ideas and the selection and retention of suitable new ideas. Neuroimaging studies suggest that the Default Mode Network contributes to the creation of new ideas while left inferior frontal and parieto-temporal cortical networks mediate the selection/retention process. Higher levels of activity in the selection/retention have been shown to be associated with stricter criteria for selection and hence the expression of fewer novel ideas. In this study, we examined the brain functional connectivity correlates of an originality score while 27 males and 27 females performed a low and a high demand visual vigilance task. Brain functional connectivity was estimated from the steady state visual evoked potential event related partial coherence. In the male group, we observed a hypothesized left frontal functional connectivity that was negatively correlated with originality in both tasks. By contrast, in the female group no significant correlation between functional connectivity and originality was observed in either task. We interpret the findings to suggest that males and females engaged different functional networks when performing the vigilance tasks. We conclude with a consideration of the possible risks when data pooling across sex in studies of higher cortical function.

Modularity and robustness of frontal cortical networks

Neural activity underlying short-term memory is maintained by interconnected networks of brain regions. It remains unknown how brain regions interact to maintain persistent activity while exhibiting robustness to corrupt information in parts of the network. We simultaneously measured activity in large neuronal populations across mouse frontal hemispheres to probe interactions between brain regions. Activity across hemispheres was coordinated to maintain coherent short-term memory. Across mice, we uncovered individual variability in the organization of frontal cortical networks. A modular organization was required for the robustness of persistent activity to perturbations: each hemisphere retained persistent activity during perturbations of the other hemisphere, thus preventing local perturbations from spreading. A dynamic gating mechanism allowed hemispheres to coordinate coherent information while gating out corrupt information. Our results show that robust short-term memory is mediated by redundant modular representations across brain regions. Redundant modular representations naturally emerge in neural network models that learned robust dynamics.

Transition of Neural Activity From the Chaotic Bipolar-Disorder State to the Periodic Healthy State Using External Feedback Signals.

Chronotherapy is a treatment for mood disorders, including major depressive disorder, mania, and bipolar disorder (BD). Neurotransmitters associated with the pathology of mood disorders exhibit circadian rhythms. A functional deficit in the neural circuits related to mood disorders disturbs the circadian rhythm; chronotherapy is an intervention that helps resynchronize the patient's biological clock with the periodic daily cycle, leading to amelioration of symptoms. In previous reports, Hadaeghi et al. proposed a non-linear dynamic model composed of the frontal and sensory cortical neural networks and the hypothalamus to explain the relationship between deficits in neural function in the frontal cortex and the disturbed circadian rhythm/mood transitions in BD (hereinafter referred to as the Hadaeghi model). In this model, neural activity in the frontal and sensory lobes exhibits periodic behavior in the healthy state; while in BD, this neural activity is in a state of chaos-chaos intermittency; this temporal departure from the healthy periodic state disturbs the circadian pacemaker in the hypothalamus. In this study, we propose an intervention based on a feedback method called the “reduced region of orbit” (RRO) method to facilitate the transition of the disturbed frontal cortical neural activity underlying BD to healthy periodic activity. Our simulation was based on the Hadaeghi model. We used an RRO feedback signal based on the return-map structure of the simulated frontal and sensory lobes to induce synchronization with a relatively weak periodic signal corresponding to the healthy condition by applying feedback of appropriate strength. The RRO feedback signal induces chaotic resonance, which facilitates the transition to healthy, periodic frontal neural activity, although this synchronization is restricted to a relatively low frequency of the periodic input signal. Additionally, applying an appropriate strength of the RRO feedback signal lowered the amplitude of the periodic input signal required to induce a synchronous state compared with the periodic signal applied alone. In conclusion, through a chaotic-resonance effect induced by the RRO feedback method, the state of the disturbed frontal neural activity characteristic of BD was transformed into a state close to healthy periodic activity by relatively weak periodic perturbations. Thus, RRO feedback-modulated chronotherapy might be an innovative new type of minimally invasive chronotherapy.

Anosognosia for limb and bucco‐facial apraxia as inferred from the recognition of gestural errors

Anosognosia is a multifaceted syndrome characterized by a lack of awareness of motor, cognitive, or emotional deficits. While most studies have focused on basic motor disorders such as hemiplegia, only recently, the issue of whether anosognosia also concerns higher-order motor disorders like apraxia has been addressed. Here, we explore the existence of a specific form of anosognosia for apraxia in forty patients with uni-hemispheric vascular lesions. The patients were requested to imitate actions involving upper limb or bucco-facial body parts and then judge their performance. Successively, they were also asked to observe video recordings of the same actions performed by themselves or by other patients and judge the accuracy of the displayed actions. The comparison of participants versus examiner judgement and between error recognition of others' versus self's actions was considered as an index of awareness deficit for the online and offline conditions, respectively. Evidence was found that awareness deficits occurred both immediately after action execution (online anosognosia) and in the video recording task (offline anosognosia). Moreover, bucco-facial and limb apraxic patients were specifically unaware of their errors in bucco-facial and limb actions, respectively, indicating for the first time a topographical organization of the syndrome. Our approach allowed us to distinguish awareness deficits from more general disorders in error recognition; indeed, anosognosic patients were able to identify errors when the same action was executed by another patient but not when the video showed their own actions. Finally, we provide evidence that anosognosia for apraxia might be associated with frontal cortical and subcortical networks.

Spontaneous Cingulate High-Current Spikes Signal Normal and Pathological Pain States.

Prominent 7-12 Hz oscillations in frontal cortical networks in rats have been reported. However, the mechanism of generation and the physiological function of this brain rhythm have not yet been clarified. Multichannel extracellular field potentials of the ACC were recorded and analyzed using the current source density method in halothane-anesthetized rats. Spontaneous high-current spikes (HCSs) were localized in the deep part of layer II/III and upper part of layer V of the ACC. The frequency of HCSs in the ACC was 7-12 Hz, with an amplitude of 6.5 ± 0.76 mV/mm2 and duration of 55.24 ± 2.43 ms. The power density significantly decreased (84.56 ± 6.93%, p < 0.05, t test) after pinching the hindpaw and significantly increased (149.28 ± 15.96%) after treatment with morphine. The suppressive effect of pinching was reversed by naloxone (0.7 mg/kg, i.p.). HCSs coincided with initiation of the depolarization of cingulate neurons and remained in a depolarized upstate. The occurrence of cingulate HCSs was persistently preceded by a hyperpolarization phase and a burst of multiunit spike activity in the medial dorsal thalamic nucleus. Spontaneous field-potential oscillations changed from 10 Hz to a lower band (i.e., ∼7.5 Hz) when a central poststroke pain condition was induced. The central poststroke pain group had a higher average coherence coefficient compared with the control group. Our results indicate that spontaneous cingulate cortical HCSs could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms in physiological and pathological pain states.SIGNIFICANCE STATEMENT This study elucidated the mechanism of generation and physiological function of prominent 7-12 Hz frequency oscillations in frontal cortical networks in rats. Spontaneous cingulate cortical high-current spikes in anesthetized rats could be initiated by thalamocortical synaptic inputs from the medial dorsal thalamic nucleus and maintained by intracortical neuronal upstate mechanisms. Suppression of the anterior cingulate cortex-filtered EEG during noxious stimulation may have resulted from the desynchronization of high-current spikes in the ACC. The enhancement of fast Fourier transform power after a systemic morphine injection suggested that the opioid system may play an important role in synchronizing cingulate cortical neuronal networks. Spontaneous cingulate high-current spikes may also play an important role in thalamocortical dysrhythmia in central poststroke pain.

Frontal Cortical Networks in Hemineglect (P3.1-024)

Frontal Cortical Networks in Hemineglect (P3.1-024)

Dopamine effects on frontal cortical blood flow and motor inhibition in Parkinson's disease

Parkinson's disease (PD) is characterized by dysfunction in frontal cortical and striatal networks that regulate action control. We investigated the pharmacological effect of dopamine agonist replacement therapy on frontal cortical activity and motor inhibition. Using Arterial Spin Labeling MRI, we examined 26 PD patients in the off- and on-dopamine agonist medication states to assess the effect of dopamine agonists on frontal cortical regional cerebral blood flow. Motor inhibition was measured by the Simon task in both medication states. We applied the dual process activation suppression model to dissociate fast response impulses from motor inhibition of incorrect responses. General linear regression model analyses determined the medication effect on regional cerebral blood flow and motor inhibition, and the relationship between regional cerebral blood flow and motor inhibitory proficiency. We show that dopamine agonist administration increases frontal cerebral blood flow, particularly in the pre-supplementary motor area (pre-SMA) and the dorsolateral prefrontal cortex (DLPFC). Higher regional blood flow in the pre-SMA, DLPFC and motor cortex was associated with better inhibitory control, suggesting that treatments which improve frontal cortical activity could ameliorate motor inhibition deficiency in PD patients.

Neural correlates of sine-wave speech intelligibility in human frontal and temporal cortex

Auditory speech comprehension is the result of neural computations that occur in a broad network that includes the temporal lobe auditory cortex and the left inferior frontal cortex. It remains unclear how representations in this network differentially contribute to speech comprehension. Here, we recorded high-density direct cortical activity during a sine-wave speech (SWS) listening task to examine detailed neural speech representations when the exact same acoustic input is comprehended versus not comprehended. Listeners heard SWS sentences (pre-exposure), followed by clear versions of the same sentences, which revealed the content of the sounds (exposure), and then the same SWS sentences again (post-exposure). Across all three task phases, high-gamma neural activity in the superior temporal gyrus was similar, distinguishing different words based on bottom-up acoustic features. In contrast, frontal regions showed a more pronounced and sudden increase in activity only when the input was comprehended, which corresponded with stronger representational separability among spatiotemporal activity patterns evoked by different words. We observed this effect only in participants who were not able to comprehend the stimuli during the pre-exposure phase, indicating a relationship between frontal high-gamma activity and speech understanding. Together, these results demonstrate that both frontal and temporal cortical networks are involved in spoken language understanding, and that under certain listening conditions, frontal regions are involved in discriminating speech sounds.

Indices of Effortful Listening Can Be Mined from Existing Electroencephalographic Data.

Studies suggest that theta (~4 to 7 Hz), alpha (~8 to 12 Hz), and stimulus-evoked dynamics of the electroencephalogram index effortful listening. Numerous auditory event-related potential datasets exist, without thorough examination of these features. The feasibility of mining those datasets for such features is assessed here. In a standard auditory-oddball paradigm, 12 listeners heard deviant high-frequency tones (10%) interspersed among low-frequency tones (90%) "near" or "far" separated in frequency. During active listening (deviance detection; experiment 1), sustained frontal midline theta power, and gamma-band inter-trial phase coherence, were greater for the near condition. No significant "near"/"far" differences were observable during passive exposure to the same sounds (experiment 2). Increased theta power likely reflects increased utilization of cognitive-control processes (e.g., working memory) that rely on frontal cortical networks. Inter-trial phase coherence differences may reflect differences in attention-modulated stimulus encoding. Reanalysis of existing datasets can usefully inform future work on listening effort.

Making the Right Connections

Recent years have seen the application of increasingly powerful transgenic, optogenetic, and chemogenetic methodologies in rodents. Armed with these tools, many studies have shown how perturbations of specific subregions of the rodent frontal cortex can elicit circumscribed behavioral phenotypes that resemble key aspects of psychiatric disorders. For example, the rodent frontal cortex can be broadly divided into motor, medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC) divisions; the mPFC can be further subdivided into prelimbic (PL), infralimbic (IL), and cingulate (Cg) cortices, while the OFC comprises the medial orbital (MO) and ventral and lateral orbital (VOLO) cortices. Recent studies have specifically linked changes in MO and VOLO activity to the expression of repetitive grooming behavior, which may model aspects of obsessive-compulsive disorder ( 1 Ahmari S.E. Spellman T. Douglass N.L. Kheirbek M.A. Simpson H.B. Deisseroth K. et al. Repeated cortico-striatal stimulation generates persistent OCD-like behavior. Science. 2013; 340: 1234-1239 Crossref PubMed Scopus (325) Google Scholar , 2 Burguiere E. Monteiro P. Feng G. Graybiel A.M. Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors. Science. 2013; 340: 1243-1246 Crossref PubMed Scopus (294) Google Scholar ), while many other studies have linked subregions of the mPFC to aspects of social behavior, cognitive flexibility, working memory, chronic pain, and anxiety. At the same time, a plethora of human brain imaging studies have implicated frontal cortical networks in a variety of neuropsychiatric disorders. Notably, the subcallosal cingulate gyrus—which includes Brodmann area 25 (a25), parts of area 24 (a24), and area 32 (a32)—has been a focus of attention since it was found that deep brain stimulation of this region can alleviate treatment-resistant depression in some patients ( 3 Hamani C. Mayberg H. Stone S. Laxton A. Haber S. Lozano A.M. The subcallosal cingulate gyrus in the context of major depression. Biol Psychiatry. 2011; 69: 301-308 Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar ). Taken together, these and numerous other studies across humans, nonhuman primates (NHPs), and rodents suggest that many psychiatric disorders may be reconceptualized as disorders of brain networks within which prefrontal or orbitofrontal regions represent key nodes. In this context, a central challenge is identifying homologies between cortical regions in humans and animal models, so that insights obtained via the use of cutting edge tools in animal models can be translated to those regions of the human brain that have been directly implicated in psychiatric disease. And while many modern neuroscientific tools can be most readily exploited in rodents, the rodent prefrontal and orbitofrontal cortices are vastly underdeveloped compared to their human counterparts. Therefore, NHPs represent a critical bridge that may facilitate the synthesis of findings across rodent and human studies. However, achieving this synthesis has been challenging. In particular, there are many possible ways to identify corresponding brain regions across species [e.g., based on cytoarchitectonic features and corticocortical connectivity ( 4 Ongur D. Price J.L. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex. 2000; 10: 206-219 Crossref PubMed Scopus (2048) Google Scholar ) or patterns of neuronal activity and behavioral functions ( 5 Seamans J.K. Lapish C.C. Durstewitz D. Comparing the prefrontal cortex of rats and primates: insights from electrophysiology. Neurotox Res. 2008; 14: 249-262 Crossref PubMed Scopus (167) Google Scholar )]. In addition, there is controversy about whether many regions of primate PFC have rodent analogs at all ( 6 Wise S.P. Forward frontal fields: phylogeny and fundamental function. Trends Neurosci. 2008; 31: 599-608 Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar ). Circuit-Based Corticostriatal Homologies Between Rat and PrimateBiological PsychiatryVol. 80Issue 7PreviewUnderstanding the neural mechanisms of psychiatric disorders requires the use of rodent models; however, frontal-striatal homologies between rodents and primates are unclear. In contrast, within the striatum, the shell of the nucleus accumbens, the hippocampal projection zone, and the amygdala projection zone (referred to as the striatal emotion processing network [EPN]) are conserved across species. We used the relationship between the EPN and projections from the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) to assess network similarities across rats and monkeys. Full-Text PDF

Resting state EEG and functional connectivity in patients with major depression and under electro-convulsive therapy

Background: Dysfunctions of neuronal circuits are involved in the pathophysiology of depression. The aim of the study was to investigate patients with major depression (MD) and matched controls using resting state EEG with respect to spectrotemporal dynamics of brain electric activity and connectivity. A subsample of patients undergoing electroconvulsive therapy (ECT) was investigated accordingly, in order to evaluate functional effects of ECT. Methods: The sample comprised 228 patients with MD, 215 matched healthy subjects, and 20 depressed subjects before and under ECT. Spectro-temporal dynamics during resting state were analysed in sensor and source space. Quantitative measures of power, asymmetry, coherence, current density and brain connectivity were calculated from artifact free EEG epochs. Results: Compared to controls patients showed an increase in delta, theta and alpha power in all brain regions with a frontal focus and significant hemispheric differences (l>r). There were increased connectivity measures for frontotemporal and parietal regions. Patients under ECT showed an increase in frontal slow activity, but a decrease in frontal hyperconnectivity. Conclusion: Dysfunctions of frontal cortical networks together with alterations of functional connectivity (hyperconnectivity) may contribute to the pathophysiology of major depression. These alterations appear to be influenced by electroconvulsive therapy.

Oscillatory dynamics coordinating human frontal networks in support of goal maintenance.

Humans have a capacity for hierarchical cognitive control—the ability to simultaneously control immediate actions while holding more abstract goals in mind. Neuropsychological and neuroimaging evidence suggests that hierarchical cognitive control emerges from a frontal architecture whereby prefrontal cortex coordinates neural activity in the motor cortices when abstract rules are needed to govern motor outcomes. Here we utilize the improved temporal resolution of human intracranial electrocorticography to investigate the mechanisms by which frontal cortical oscillatory networks communicate in support of hierarchical cognitive control. Responding according to progressively more abstract rules results in greater frontal network theta phase encoding (4-8 Hz) and increased prefrontal local neuronal population activity (high gamma amplitude, 80-150 Hz), which predicts trial-by-trial response times. Theta phase encoding couples with high gamma amplitude during interregional information encoding, suggesting that interregional phase encoding is a mechanism for the dynamic instantiation of complex cognitive functions by frontal cortical subnetworks.

Understanding cross-modal interactions of spatial and temporal information from a cortical perspective

In the ventriloquism effect, perception of visual spatial information biases judgments of auditory events, yet there is little effect of auditory stimuli on perception of visual locations. In the flash-beep illusion, the number of auditory “beeps” biases judgments of the count of visual flashes, but visual flashes have little effect on perceived number of auditory events. These asymmetries suggest that vision is the “natural” sensory modality for coding spatial information, while audition is specialized for representing temporal information. Here, we review recent behavioral and neuroimaging evidence from our labs exploring the neural underpinnings of such perceptual asymmetries. Specifically, we find that there are distinct frontal cortical networks associated with visual information and auditory information. Yet these networks can be recruited by the other sensory modality, depending on task demands. For instance, when judging spatial aspects of auditory inputs, neural areas associated with visual processing are recruited; when judging temporal aspects of visual inputs, areas associated with auditory processing are activated. We also find another asymmetry: knowing when a spatial event is going to occur helps listeners judge location, but knowing where an event will occur does not help judgments about that event's timing. These kinds of studies help elucidate how temporal and spatial information is encoded in the brain, and the neural mechanisms by which visual-spatial and auditory-temporal information interact.

Frontal midline θ power as an index of listening effort.

Attempts to identify physiological correlates of listening effort have mainly focused on peripheral measures (e.g. pupillometry) and auditory-evoked/event-related potentials. Although nonauditory studies have suggested that sustained time-frequency electroencephalographic (EEG) features in the θ-band (4-7 Hz) are correlated with domain-general mental effort, little work has characterized such features during effortful listening. Here, high-density EEG data was collected while listeners performed a sentence-recognition task in noise, the signal-to-noise ratio (SNR) of which varied across blocks. Frontal midline θ (Fmθ), largely driven by sources localized in or near the medial frontal cortex, showed greater power with decreasing SNR and was positively correlated with self-reports of effort. Increased Fmθ was present before speech onset and during speech presentation. Fmθ power also differed across SNRs when including only trials in which all words were recognized, suggesting that the effects were unrelated to performance differences. Results suggest that frontal cortical networks play a larger role in listening as acoustic signals are increasingly masked. Further, sustained time-frequency EEG features may usefully supplement previously used peripheral and event-related potential measures in psychophysiological investigations of effortful listening.

Role of perinatal long-chain omega-3 fatty acids in cortical circuit maturation: Mechanisms and implications for psychopathology.

Accumulating translational evidence suggests that the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) plays a role in the maturation and stability of cortical circuits that are impaired in different recurrent psychiatric disorders. Specifically, rodent and cell culture studies find that DHA preferentially accumulates in synaptic and growth cone membranes and promotes neurite outgrowth, dendritic spine stability, and synaptogenesis. Additional evidence suggests that DHA may play a role in microglia-mediated synaptic pruning, as well as myelin development and resilience. In non-human primates n-3 fatty acid insufficiency during perinatal development leads to widespread deficits in functional connectivity in adult frontal cortical networks compared to primates raised on DHA-fortified diet. Preterm delivery in non-human primates and humans is associated with early deficits in cortical DHA accrual. Human preterm birth is associated with long-standing deficits in myelin integrity and cortical circuit connectivity and increased risk for attention deficit/hyperactivity disorder (ADHD), mood, and psychotic disorders. In general, ADHD and mood and psychotic disorders initially emerge during rapid periods of cortical circuit maturation and are characterized by DHA deficits, myelin pathology, and impaired cortical circuit connectivity. Together these associations suggest that early and uncorrected deficits in fetal brain DHA accrual may represent a modifiable risk factor for cortical circuit maturation deficits in psychiatric disorders, and could therefore have significant implications for informing early intervention and prevention strategies.

Brain dynamics that correlate with effects of learning on auditory distance perception.

Accuracy in auditory distance perception can improve with practice and varies for sounds differing in familiarity. Here, listeners were trained to judge the distances of English, Bengali, and backwards speech sources pre-recorded at near (2-m) and far (30-m) distances. Listeners' accuracy was tested before and after training. Improvements from pre-test to post-test were greater for forward speech, demonstrating a learning advantage for forward speech sounds. Independent component (IC) processes identified in electroencephalographic (EEG) data collected during pre- and post-testing revealed three clusters of ICs across subjects with stimulus-locked spectral perturbations related to learning and accuracy. One cluster exhibited a transient stimulus-locked increase in 4–8 Hz power (theta event-related synchronization; ERS) that was smaller after training and largest for backwards speech. For a left temporal cluster, 8–12 Hz decreases in power (alpha event-related desynchronization; ERD) were greatest for English speech and less prominent after training. In contrast, a cluster of IC processes centered at or near anterior portions of the medial frontal cortex showed learning-related enhancement of sustained increases in 10–16 Hz power (upper-alpha/low-beta ERS). The degree of this enhancement was positively correlated with the degree of behavioral improvements. Results suggest that neural dynamics in non-auditory cortical areas support distance judgments. Further, frontal cortical networks associated with attentional and/or working memory processes appear to play a role in perceptual learning for source distance.

Allosteric Modulators for the Treatment of Schizophrenia: Targeting Glutamatergic Networks

Schizophrenia is a highly debilitating mental disorder which afflicts approximately 1% of the global population. Cognitive and negative deficits account for the lifelong disability associated with schizophrenia, whose symptoms are not effectively addressed by current treatments. New medicines are needed to treat these aspects of the disease. Neurodevelopmental, neuropathological, genetic, and behavioral pharmacological data indicate that schizophrenia stems from a dysfunction of glutamate synaptic transmission, particularly in frontal cortical networks. A number of novel pre- and postsynaptic mechanisms affecting glutamatergic synaptic transmission have emerged as viable targets for schizophrenia. While developing orthosteric glutamatergic agents for these targets has proven extremely difficult, targeting allosteric sites of these targets has emerged as a promising alternative. From a medicinal chemistry perspective, allosteric sites provide an opportunity of finding agents with better drug-like properties and greater target specificity. Furthermore, allosteric modulators are better suited to maintaining the highly precise temporal and spatial aspects of glutamatergic synaptic transmission. Herein, we review neuropathological and genomic/genetic evidence underscoring the importance of glutamate synaptic dysfunction in the etiology of schizophrenia and make a case for allosteric targets for therapeutic intervention. We review progress in identifying allosteric modulators of AMPA receptors, NMDA receptors, and metabotropic glutamate receptors, all with the aim of restoring physiological glutamatergic synaptic transmission. Challenges remain given the complexity of schizophrenia and the difficulty in studying cognition in animals and humans. Nonetheless, important compounds have emerged from these efforts and promising preclinical and variable clinical validation has been achieved.

Real-Time Parallel Processing of Grammatical Structure in the Fronto-Striatal System: A Recurrent Network Simulation Study Using Reservoir Computing

Sentence processing takes place in real-time. Previous words in the sentence can influence the processing of the current word in the timescale of hundreds of milliseconds. Recent neurophysiological studies in humans suggest that the fronto-striatal system (frontal cortex, and striatum – the major input locus of the basal ganglia) plays a crucial role in this process. The current research provides a possible explanation of how certain aspects of this real-time processing can occur, based on the dynamics of recurrent cortical networks, and plasticity in the cortico-striatal system. We simulate prefrontal area BA47 as a recurrent network that receives on-line input about word categories during sentence processing, with plastic connections between cortex and striatum. We exploit the homology between the cortico-striatal system and reservoir computing, where recurrent frontal cortical networks are the reservoir, and plastic cortico-striatal synapses are the readout. The system is trained on sentence-meaning pairs, where meaning is coded as activation in the striatum corresponding to the roles that different nouns and verbs play in the sentences. The model learns an extended set of grammatical constructions, and demonstrates the ability to generalize to novel constructions. It demonstrates how early in the sentence, a parallel set of predictions are made concerning the meaning, which are then confirmed or updated as the processing of the input sentence proceeds. It demonstrates how on-line responses to words are influenced by previous words in the sentence, and by previous sentences in the discourse, providing new insight into the neurophysiology of the P600 ERP scalp response to grammatical complexity. This demonstrates that a recurrent neural network can decode grammatical structure from sentences in real-time in order to generate a predictive representation of the meaning of the sentences. This can provide insight into the underlying mechanisms of human cortico-striatal function in sentence processing.