Phase precession in the human hippocampus and entorhinal cortex.

Knowing where we are, where we have been, and where we are going is critical to many behaviors, including navigation and memory. One potential neuronal mechanism underlying this ability is phase precession, in which spatially tuned neurons represent sequences of positions by activating at progressively earlier phases of local network theta oscillations. Based on studies in rodents, researchers have hypothesized that phase precession may be a general neural pattern for representing sequential events for learning and memory. By recording human single-neuron activity during spatial navigation, we show that spatially tuned neurons in the human hippocampus and entorhinal cortex exhibit phase precession. Furthermore, beyond the neural representation of locations, we show evidence for phase precession related to specific goal states. Our findings thus extend theta phase precession to humans and suggest that this phenomenon has a broad functional role for the neural representation of both spatial and non-spatial information.

Representational geometry of perceptual decisions in the monkey parietal cortex.

Lateral intraparietal (LIP) neurons represent formation of perceptual decisions involving eye movements. In circuit models for these decisions, neural ensembles that encode actions compete to form decisions. Consequently, representation and readout of the decision variables (DVs) are implemented similarly for decisions with identical competing actions, irrespective of input and task context differences. Further, DVs are encoded as partially potentiated action plans through balance of activity of action-selective ensembles. Here, we test those core principles. We show that in a novel face-discrimination task, LIP firing rates decrease with supporting evidence, contrary to conventional motion-discrimination tasks. These opposite response patterns arise from similar mechanisms in which decisions form along curved population-response manifolds misaligned with action representations. These manifolds rotate in state space based on context, indicating distinct optimal readouts for different tasks. We show similar manifolds in lateral and medial prefrontal cortices, suggesting similar representational geometry across decision-making circuits.

Correlated Neural Activity across the Brains of Socially Interacting Bats.

Social interactions occur between multiple individuals, but what is the detailed relationship between the neural dynamics across their brains? To address this question across timescales and levels of neural activity, we used wireless electrophysiology to simultaneously record from pairs of bats engaged in a wide range of natural social interactions. We found that neural activity was remarkably correlated between their brains over timescales from seconds to hours. The correlation depended on a shared social environment and was most prominent in high frequency local field potentials (>30 Hz), followed by local spiking activity. Furthermore, the degree of neural correlation covaried with the extent of social interactions, and an increase in correlation preceded their initiation. These results show that inter-brain correlation is an inherent feature of natural social interactions, reveal the domain of neural activity where it is most prominent, and provide a foundation for studying its functional role in social behaviors.

Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems.

The dorsal raphe (DR) constitutes a major serotonergic input to the forebrain and modulates diverse functions and brain states, including mood, anxiety, and sensory and motor functions. Most functional studies to date have treated DR serotonin neurons as a single population. Using viral-genetic methods, we found that subcortical- and cortical-projecting serotonin neurons have distinct cell-body distributions within the DR and differentially co-express a vesicular glutamate transporter. Further, amygdala- and frontal-cortex-projecting DR serotonin neurons have largely complementary whole-brain collateralization patterns, receive biased inputs from presynaptic partners, and exhibit opposite responses to aversive stimuli. Gain- and loss-of-function experiments suggest that amygdala-projecting DR serotonin neurons promote anxiety-like behavior, whereas frontal-cortex-projecting neurons promote active coping in the face of challenge. These results provide compelling evidence that the DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioral functions.

Transcranial magnetic stimulation to frontal but not occipital cortex disrupts endogenous attention.

Covert endogenous (voluntary) attention improves visual performance. Human neuroimaging studies suggest that the putative human homolog of macaque frontal eye fields (FEF+) is critical for this improvement, whereas early visual areas are not. Yet, correlational MRI methods do not manipulate brain function. We investigated whether rFEF+ or V1/V2 plays a causal role in endogenous attention. We used transcranial magnetic stimulation (TMS) to alter activity in the visual cortex or rFEF+ when observers performed an orientation discrimination task while attention was manipulated. On every trial, they received double-pulse TMS at a predetermined site (stimulated region) around V1/V2 or rFEF+. Two cortically magnified gratings were presented, one in the stimulated region (contralateral to the stimulated area) and another in the symmetric (ipsilateral) nonstimulated region. Grating contrast was varied to measure contrast response functions (CRFs) for all attention and stimulation combinations. In experiment 1, the CRFs were similar at the stimulated and nonstimulated regions, indicating that early visual areas do not modulate endogenous attention during stimulus presentation. In contrast, occipital TMS eliminates exogenous (involuntary) attention effects on performance [A. Fernández, M. Carrasco,Curr. Biol. 30, 4078-4084 (2020)]. In experiment 2, rFEF+ stimulation decreased the overall attentional effect; neither benefits at the attended location nor costs at the unattended location were significant. The frequency and directionality of microsaccades mimicked this pattern: Whereas occipital stimulation did not affect microsaccades, rFEF+ stimulation caused a higher microsaccade rate directed toward the stimulated hemifield. These results provide causal evidence of the role of this frontal region for endogenous attention.

Neural Representations of Post-Decision Accuracy and Reward Expectation in the Caudate Nucleus and Frontal Eye Field.

Performance monitoring that supports ongoing behavioral adjustments is often examined in the context of either choice confidence for perceptual decisions (i.e., "did I get it right?") or reward expectation for reward-based decisions (i.e., "what reward will I receive?"). However, our understanding of how the brain encodes these distinct evaluative signals remains limited because they are easily conflated, particularly in commonly used two-alternative tasks with symmetric rewards for correct choices. Previously we used a motion-discrimination task with asymmetric rewards to identify neural substrates of forming reward-biased perceptual decisions in the caudate nucleus (part of the striatum in the basal ganglia) and the frontal eye field (FEF, in prefrontal cortex). Here we leveraged this task design to partially decouple estimates of accuracy and reward expectation and examine their impacts on subsequent decisions and their representations in those two brain areas. We identified distinguishable representations of these two evaluative signals in individual caudate and FEF neurons, with regional differences in their distribution patterns and time courses. We observed that well-trained monkeys (both sexes) used both evaluative signals, infrequently but consistently, to adjust their subsequent decisions. We found further that these behavioral adjustments had reliable relationships with the neural representations of both evaluative signals in caudate, but not FEF. These results suggest that the cortico-striatal decision network may use diverse evaluative signals to monitor and adjust decision-making behaviors, adding to our understanding of the different roles that the FEF and caudate nucleus play in a diversity of decision-related computations.

Oscillatory Waveform Shape and Temporal Spike Correlations Differ across Bat Frontal and Auditory Cortex.

Neural oscillations are associated with diverse computations in the mammalian brain. The waveform shape of oscillatory activity measured in the cortex relates to local physiology and can be informative about aberrant or dynamically changing states. However, how waveform shape differs across distant yet functionally and anatomically related cortical regions is largely unknown. In this study, we capitalize on simultaneous recordings of local field potentials (LFPs) in the auditory and frontal cortices of awake, male Carollia perspicillata bats to examine, on a cycle-by-cycle basis, waveform shape differences across cortical regions. We find that waveform shape differs markedly in the fronto-auditory circuit even for temporally correlated rhythmic activity in comparable frequency ranges (i.e., in the delta and gamma bands) during spontaneous activity. In addition, we report consistent differences between areas in the variability of waveform shape across individual cycles. A conceptual model predicts higher spike-spike and spike-LFP correlations in regions with more asymmetric shapes, a phenomenon that was observed in the data: spike-spike and spike-LFP correlations were higher in the frontal cortex. The model suggests a relationship between waveform shape differences and differences in spike correlations across cortical areas. Altogether, these results indicate that oscillatory activity in the frontal and auditory cortex possesses distinct dynamics related to the anatomical and functional diversity of the fronto-auditory circuit.

A special role for anterior cingulate cortex, but not orbitofrontal cortex or basolateral amygdala, in choices involving information.

Subjects are often willing to pay a cost for information. In a procedure that promotes paradoxical choices, animals choose between a richer option followed by a cue that is rewarded 50% of the time (No Info) vs. a leaner option followed by one of two cues that signal certain outcomes: one always rewarded (100%) and the other never rewarded, 0% (Info). Since decisions involve comparing the subjective value of options after integrating all their features, preference for information may rely on cortico-amygdalar circuitry. To test this, male and female rats were prepared with bilateral inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in the anterior cingulate cortex, orbitofrontal cortex, basolateral amygdala, or null virus (control). We inhibited these regions after stable preference was acquired. We found that inhibition of the anterior cingulate cortex destabilized choice preference in female rats without affecting latency to choose or response rate to cues. A logistic regression fit revealed that previous choice predicted current choice in all conditions, however previously rewarded Info trials strongly predicted preference in all conditions except in female rats following anterior cingulate cortex inhibition. The results reveal a causal, sex-dependent role for the anterior cingulate cortex in decisions involving information.

Dorsomedial frontal cortex damage impairs error-based, but not reinforcement-based motor learning in humans.

We adapt our movements to new and changing environments through multiple processes. Sensory error-based learning counteracts environmental perturbations that affect the sensory consequences of movements. Sensory errors also cause the upregulation of reflexes and muscle co-contraction. Reinforcement-based learning enhances the selection of movements that produce rewarding outcomes. Although some findings have identified dissociable neural substrates of sensory error- and reinforcement-based learning, correlative methods have implicated dorsomedial frontal cortex in both. Here, we tested the causal contributions of dorsomedial frontal to adaptive motor control, studying people with chronic damage to this region. Seven human participants with focal brain lesions affecting the dorsomedial frontal and 20 controls performed a battery of arm movement tasks. Three experiments tested: (i) the upregulation of visuomotor reflexes and muscle co-contraction in response to unpredictable mechanical perturbations, (ii) sensory error-based learning in which participants learned to compensate predictively for mechanical force-field perturbations, and (iii) reinforcement-based motor learning based on binary feedback in the absence of sensory error feedback. Participants with dorsomedial frontal damage were impaired in the early stages of force field adaptation, but performed similarly to controls in all other measures. These results provide evidence for a specific and selective causal role for the dorsomedial frontal in sensory error-based learning.

Fractionating difficulty during sentence comprehension using functional neuroimaging.

Sentence comprehension is highly practiced and largely automatic, but this belies the complexity of the underlying processes. We used functional neuroimaging to investigate garden-path sentences that cause difficulty during comprehension, in order to unpack the different processes used to support sentence interpretation. By investigating garden-path and other types of sentences within the same individuals, we functionally profiled different regions within the temporal and frontal cortices in the left hemisphere. The results revealed that different aspects of comprehension difficulty are handled by left posterior temporal, left anterior temporal, ventral left frontal, and dorsal left frontal cortices. The functional profiles of these regions likely lie along a spectrum of specificity to generality, including language-specific processing of linguistic representations, more general conflict resolution processes operating over linguistic representations, and processes for handling difficulty in general. These findings suggest that difficulty is not unitary and that there is a role for a variety of linguistic and non-linguistic processes in supporting comprehension.

SELENBP1 overexpression in the prefrontal cortex underlies negative symptoms of schizophrenia.

The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.

Mothers and fathers show different neural synchrony with their children during shared experiences.

Parent-child shared experiences has an important influence on social development in children although contributions of mothers and fathers may differ. Neural synchronicity occurs between mothers and fathers and their children during social interactions but it is unclear whether they differ in this respect. We used data from simultaneous fNIRS hyperscanning in mothers (n = 33) and fathers (n = 29) and their children (3-4 years) to determine different patterns and strengths of neural synchronization in the frontal cortex during co-viewing of videos or free-play. Mothers showed greater synchrony with child than fathers during passive viewing of videos and the synchronization was positively associated with video complexity and negatively associated with parental stress. During play interactions, mothers showed more controlling behaviors over their child and greater evidence for joint gaze and joint imitation play with child whereas fathers spent more time gazing at other things. In addition, different aspects of child communication promoted neural synchrony between mothers and fathers and child during active play interactions. Overall, our findings indicate greater neural and behavioral synchrony between mothers than fathers and young children during passive or active shared experiences, although for both it was weakened by parental distress and child difficulty.

A perspective on epigenomic aging processes in the human brain and their plasticity in patients with mental disorders - a systematic review.

The debate surrounding nature versus nurture remains a central question in neuroscience, psychology, and in psychiatry, holding implications for both aging processes and the etiology of mental illness. Epigenetics can serve as a bridge between genetic predisposition and environmental influences, thus offering a potential avenue for addressing these questions. Epigenetic clocks, in particular, offer a theoretical framework for measuring biological age based on DNA methylation signatures, enabling the identification of disparities between biological and chronological age. This structured review seeks to consolidate current knowledge regarding the relationship between mental disorders and epigenetic age within the brain. Through a comprehensive literature search encompassing databases such as EBSCO, PubMed, and ClinicalTrials.gov, relevant studies were identified and analyzed. Studies that met inclusion criteria were scrutinized, focusing on those with large sample sizes, analyses of both brain tissue and blood samples, investigation of frontal cortex markers, and a specific emphasis on schizophrenia and depressive disorders. Our review revealed a paucity of significant findings, yet notable insights emerged from studies meeting specific criteria. Studies characterized by extensive sample sizes, analysis of brain tissue and blood samples, assessment of frontal cortex markers, and a focus on schizophrenia and depressive disorders yielded particularly noteworthy results. Despite the limited number of significant findings, these studies shed light on the complex interplay between epigenetic aging and mental illness. While the current body of literature on epigenetic aging in mental disorders presents limited significant findings, it underscores the importance of further research in this area. Future studies should prioritize large sample sizes, comprehensive analyses of brain tissue and blood samples, exploration of specific brain regions such as the frontal cortex, and a focus on key mental disorders. Such endeavors will contribute to a deeper understanding of the relationship between epigenetic aging and mental illness, potentially informing novel diagnostic and therapeutic approaches.

In situ analysis of neuronal injury and neuroinflammation during HIV-1 infection.

BACKGROUND: Since the introduction of combination antiretroviral therapy (cART) the brain has become an important human immunodeficiency virus (HIV) reservoir due to the relatively low penetration of many drugs utilized in cART into the central nervous system (CNS). Given the inherent limitations of directly assessing acute HIV infection in the brains of people living with HIV (PLWH), animal models, such as humanized mouse models, offer the most effective means of studying the effects of different viral strains and their impact on HIV infection in the CNS. To evaluate CNS pathology during HIV-1 infection in the humanized bone marrow/liver/thymus (BLT) mouse model, a histological analysis was conducted on five CNS regions, including the frontal cortex, hippocampus, striatum, cerebellum, and spinal cord, to delineate the neuronal (MAP2ab, NeuN) and neuroinflammatory (GFAP, Iba-1) changes induced by two viral strains after 2 weeks and 8 weeks post-infection. RESULTS: Findings reveal HIV-infected human cells in the brain of HIV-infected BLT mice, demonstrating HIV neuroinvasion. Further, both viral strains, HIV-1JR-CSF and HIV-1CH040, induced neuronal injury and astrogliosis across all CNS regions following HIV infection at both time points, as demonstrated by decreases in MAP2ab and increases in GFAP fluorescence signal, respectively. Importantly, infection with HIV-1JR-CSF had more prominent effects on neuronal health in specific CNS regions compared to HIV-1CH040 infection, with decreasing number of NeuN+ neurons, specifically in the frontal cortex. On the other hand, infection with HIV-1CH040 demonstrated more prominent effects on neuroinflammation, assessed by an increase in GFAP signal and/or an increase in number of Iba-1+ microglia, across CNS regions. CONCLUSION: These findings demonstrate that CNS pathology is widespread during acute HIV infection. However, neuronal loss and the magnitude of neuroinflammation in the CNS is strain dependent indicating that strains of HIV cause differential CNS pathologies.

Exploring the parity paradox: Differential effects on neuroplasticity and inflammation by APOEe4 genotype at middle age.

Female sex and Apolipoprotein E (APOE) ε4 genotype are top non-modifiable risk factors for Alzheimer's disease (AD). Although female-unique experiences like parity (pregnancy and motherhood) have positive effects on neuroplasticity at middle age, previous pregnancy may also contribute to AD risk. To explore these seemingly paradoxical long-term effects of parity, we investigated the impact of parity with APOEε4 genotype by examining behavioural and neural biomarkers of brain health in middle-aged female rats. Our findings show that primiparous (parous one time) hAPOEε4 rats display increased use of a non-spatial cognitive strategy and exhibit decreased number and recruitment of new-born neurons in the ventral dentate gyrus of the hippocampus in response to spatial working memory retrieval. Furthermore, primiparity and hAPOEε4 genotype synergistically modulate inflammatory markers in the ventral hippocampus. Collectively, these findings demonstrate that previous parity in hAPOEε4 rats confers an added risk to present with reduced activity and engagement of the hippocampus as well as elevated pro-inflammatory signaling, and underscore the importance of considering female-specific factors and genotype in health research.

Valproate use associated with frontal and cerebellar gray matter volume reductions: A voxel-based morphometry study.

Recent morphometric magnetic resonance imaging (MRI) studies suggested the possibility that valproate (VPA) use is associated with parieto-occipital cortical thinning in patients with heterogeneous epilepsy syndromes. In this study, we examined the effect of VPA on the brain volume using a large number of homogenous patients with idiopathic generalized epilepsy. Voxel-based morphometry was used to compare regional gray matter (GM) volume between 112 patients currently taking VPA (VPA+ group), 81 patients not currently taking VPA (VPA- group), and 120 healthy subjects (control group). The VPA+ group showed a significant GM volume reduction in the bilateral cerebellum, hippocampus, insula, caudate nucleus, medial frontal cortex/anterior cingulate cortex, primary motor/premotor cortex, medial occipital cortex, and anteromedial thalamus, as compared to the control group. The VPA- group showed a significant GM volume reduction in the anteromedial thalamus and right hippocampus/temporal cortex, as compared to the control group. Compared to the VPA- group, the VPA+ group had a significant GM volume reduction in the bilateral cerebellum, primary motor/premotor cortex, and medial frontal cortex/anterior cingulate cortex. We have provided evidence that VPA use could result in GM volume reductions in the frontal cortex and cerebellum. Our findings should be acknowledged as a potential confounding factor in morphometric MRI studies that include subjects taking VPA.

Beyond peaks and troughs: Multiplexed performance monitoring signals in the EEG.

With the discovery of event-related potentials elicited by errors more than 30 years ago, a new avenue of research on performance monitoring, cognitive control, and decision making emerged. Since then, the field has developed and expanded fulminantly. After a brief overview on the EEG correlates of performance monitoring, this article reviews recent advancements based on single-trial analyses using independent component analysis, multiple regression, and multivariate pattern classification. Given the close interconnection between performance monitoring and reinforcement learning, computational modeling and model-based EEG analyses have made a particularly strong impact. The reviewed findings demonstrate that error- and feedback-related EEG dynamics represent variables reflecting how performance-monitoring signals are weighted and transformed into an adaptation signal that guides future decisions and actions. The model-based single-trial analysis approach goes far beyond conventional peak-and-trough analyses of event-related potentials and enables testing mechanistic theories of performance monitoring, cognitive control, and decision making.

CBD treatment following early life seizures alters orbitofrontal-striatal signaling during adulthood.

Obsessive compulsive disorder (OCD) is a comorbid condition of epilepsy and often adds to the burden of epilepsy. Both OCD and epilepsy are disorders of hyperexcitable circuits. Fronto-striatal circuit dysfunction is implicated in OCD. Prior work in our laboratory has shown that in rat pups following a series of flurothyl-induced early life seizures (ELS) exhibit frontal-lobe dysfunction along with alterations in electrographic temporal coordination between the orbitofrontal cortex (OFC) and dorsomedial striatum (DMS), circuits implicated in OCD. Here, we studied the effects of ELS in male and female rat pups on OCD-like behaviors as adults using the marble burying test (MBT). Because cannabidiol (CBD) is an effective antiseizure medication and has shown efficacy in the treatment of individuals with OCD, we also randomized rats to CBD or vehicle treatment following ELS to determine if CBD had any effect on OCD-like behaviors. While the flurothyl model of ELS did not induce OCD-like behaviors, as measured in the MBT, ELS did alter neural signaling in structures implicated in OCD and CBD had sex-dependent effects of temporal coordination in a way which suggests it may have a beneficial effect on epilepsy-related OCD.

Distinct neurocognitive mechanisms underlying learning and representations of symbols of life and death.

Life and death are 2 fundamental concepts regarding existence of organisms. People often signify these concepts using symbols to facilitate communications, but how the brain learns and represents these symbols remains unclear. In the present study, we quantified behavioral and brain responses during learning associations between words ("life" or "death") with shapes as concrete referents. Behavioral responses to word-shape pairs showed an affirmative response bias to life-shape pairs but a denial response bias to death-shape pairs. Multimodal brain imaging results revealed that the right frontal and dorsal cingulate cortices monitored these response biases, respectively. Moreover, relative to unlearned shapes, life-related shapes induced increased alpha (9-14 Hz) oscillations in the right parietal cortex and precuneus, whereas death-related shapes enhanced beta (15-30 Hz) oscillations in the left parietal cortex, superior temporal sulcus, and precuneus. Our findings unraveled distinct neurocognitive mechanisms underlying learning and representations of concrete referents of life and death concepts.

A dissociable functional relevance of theta- and beta-band activities during complex sensorimotor integration.

Sensorimotor integration processes play a central role in daily life and require that different sources of sensory information become integrated: i.e. the information related to the object being under control of the agent (i.e. indicator) and the information about the goal of acting. Yet, how this is accomplished on a neurophysiological level is contentious. We focus on the role of theta- and beta-band activities and examine which neuroanatomical structures are involved. Healthy participants (n = 41) performed 3 consecutive pursuit-tracking EEG experiments in which the source of visual information available for tracking was varied (i.e. that of the indicator and the goal of acting). The initial specification of indicator dynamics is determined through beta-band activity in parietal cortices. When information about the goal was not accessible, but operating the indicator was required nevertheless, this incurred increased theta-band activity in the superior frontal cortex, signaling a higher need for control. Later, theta- and beta-band activities encode distinct information within the ventral processing stream: Theta-band activity is affected by the indicator information, while beta-band activity is affected by the information about the action goal. Complex sensorimotor integration is realized through a cascade of theta- and beta-band activities in a ventral-stream-parieto-frontal network.