Associations of tau, Aß, and brain volume of the Papez circuit with cognition in Alzheimer's disease.

This study aimed to investigate the cross-sectional associations between regional Alzheimer's disease (AD) biomarkers, including tau, ß-amyloid (Aß), and brain volume, within the Papez circuit, and neuropsychological functioning across the preclinical and clinical spectrum of AD. We utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 251 Aß-positive participants. Participants were categorized into three groups based on the Clinical Dementia Rating (CDR): 73 individuals with preclinical AD (CDR = 0), 114 with prodromal AD (CDR = 0.5), and 64 with clinical AD dementia (CDR ≥ 1). Linear regression analyses, adjusted for age, gender, and education years, were employed to evaluate the associations between five regions of interest (the hippocampus, para-hippocampus, entorhinal cortex, posterior cingulate cortex, and thalamus) and five neuropsychological tests across the three imaging modalities. In the preclinical stage of AD, flortaucipir PET was associated with impaired global cognition and episodic memory (range standardized ß = 0.255-0.498, p < 0.05 corrected for multiple comparisons), while florbetapir PET and brain volume were marginally related to global cognition (range standardized ß = 0.221-0.231, p < 0.05). In the clinical stages of AD (prodromal and dementia), both increased flortaucipir uptake and decreased brain volume were significantly associated with poorer global neuropsychological and episodic memory performance (range standardized ß = 0.222-0.621, p < 0.05, most regions of interest survived correction for multiple comparisions). However, a slight relationship was observed between florbetapir uptake and poorer global cognitive function. The regions most affected by flortaucipir PET were the hippocampus, para-hippocampus, and posterior cingulate cortex. During the clinical stages, the hippocampus and entorhinal cortex exhibited the most significant volumetric changes. Tau PET and brain volume measurements within the Papez circuit are more sensitive indicators of early cognitive deficits in AD than Aß PET. Furthermore, during the clinical stages of AD, both flortaucipir PET and brain volume of the Papez circuit are closely correlated with cognitive decline. These findings underscore the importance of integrating multiple biomarkers for the comprehensive evaluation of AD pathology and its impact on cognition.

Alteration in resting-state effective connectivity within the Papez circuit in Presbycusis.

Previous studies have suggested that the Papez circuit may be involved in the cognitive impairment observed after hearing loss in presbycusis patients, yet relatively little is known about the pattern of changes in effective connectivity within the circuit. The aim of this study was to investigate abnormal alterations in resting-state effective connectivity within the Papez circuit and their association with cognitive decline in presbycusis patients. The spectral dynamic causal modelling (spDCM) approach was used for resting-state effective connectivity analysis in 61 presbycusis patients and 52 healthy controls (HCs) within the Papez circuit. The hippocampus (HPC), mamillary body (MB), anterior thalamic nuclei (ATN), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), entorhinal cortex (ERC), subiculum (Sub) and parahippocampal gyrus (PHG) were selected as the regions of interest (ROIs). The fully connected model difference in effective connectivity between the two groups was assessed, and the correlation between effective connectivity alteration and cognitive scale was analysed. We found that presbycusis patients demonstrated decreased effective connectivity from MB, PCC, and Sub to ACC relative to HCs, whereas higher effective connectivity strength was shown from HPC to MB, from ATN to PHG and from PHG to Sub. The effective connectivity from PHG to Sub was significantly negatively correlated with the complex figure test (CFT)-delay score (rho = -0.259, p = 0.044). The results support and reinforce the role of abnormal effective connectivity within the Papez circuit in the pathophysiology of presbycusis-related cognitive impairment and reveal its potential as a novel imaging marker.

Computerized Cognitive Training Enhances Episodic Memory by Down-Modulating Posterior Cingulate-Precuneus Connectivity in Older Persons With Mild Cognitive Impairment: A Randomized Controlled Trial.

OBJECTIVE: The neural mechanisms underlying the beneficial effects of a computerized cognitive training (CCT) program for improving episodic memory in older persons with mild cognitive impairment (MCI) remain unclear. This study aimed to use both functional and structural brain changes to elucidate the treatment effects of CCT on enhancing episodic memory. DESIGN, SETTING, AND PARTICIPANTS: Single-blinded, multicenter randomized controlled trial on 60 older adults with MCI in Fuzhou, China. INTERVENTION: Participants were randomly assigned to either an 8-week 24-hour CCT program or a health education program as the control. MEASUREMENTS: Clinical outcomes included changes in scores on the immediate and/or delayed recall subtests of the Chinese auditory verbal learning test (CAVLT) and rey complex figure test (CFT), and changes in gray matter volume and the functional connectivity of the posterior cingulate cortex (PCC) and hippocampus in the Papez circuit on magnetic resonance imaging. RESULTS: Significant group-by-time effects showed greater improvements in both immediate and delayed recall scores of CAVLT and delayed recall scores of Rey CFT in participants receiving the CCT program compared to those in the health education program. Among the CCT participants, seed-based analyses revealed decreases in functional connectivity of the PCC and hippocampus with neural substrates in the parietal and occipital regions. The decreased PCC and precuneus connectivity were found to mediate patients' improvements in immediate recall function. CONCLUSION: An 8-week CCT program was effective for improving episodic memory in older individuals with MCI. The decrease in connectivity originating from the PCC and hippocampus is suggestive of potential plastic changes in the Papez circuit, which could have alleviated the age-related compensatory mechanism. The findings of this study also shed light on expanding the content and extending the frequency and duration of the CCT program in future studies.

The APOE4 effect: structural brain differences in Alzheimer's disease according to the age at symptom onset.

BACKGROUND AND PURPOSE: How the APOE genotype can differentially affect cortical and subcortical memory structures in biomarker-confirmed early-onset (EOAD) and late-onset (LOAD) Alzheimer's disease (AD) was assessed. METHOD: Eighty-seven cerebrospinal fluid (CSF) biomarker-confirmed AD patients were classified according to their APOE genotype and age at onset. 28 were EOAD APOE4 carriers (+EOAD), 21 EOAD APOE4 non-carriers (-EOAD), 23 LOAD APOE4 carriers (+LOAD) and 15 LOAD APOE4 non-carriers (-LOAD). Grey matter (GM) volume differences were analyzed using voxel-based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition. RESULTS: Significantly more mammillary body atrophy in +EOAD compared to -EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in +LOAD compared to -LOAD. Medial temporal GM volume loss was also found in +EOAD compared to -LOAD. With an exception for +EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in -LOAD. CONCLUSIONS: Our results show that the APOE genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD APOE4 genotype is mostly associated with increased medial temporal and parietal atrophy compared to -LOAD, for EOAD APOE4 might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that APOE genotype needs to be taken into account when classifying patients by age at onset.

The Cortico-Limbo-Thalamo-Cortical Circuits: An Update to the Original Papez Circuit of the Human Limbic System.

The Papez circuit, first proposed by James Papez in 1937, is a circuit believed to control memory and emotions, composed of the cingulate cortex, entorhinal cortex, parahippocampal gyrus, hippocampus, hypothalamus, and thalamus. Pursuant to James Papez, Paul Yakovlev and Paul MacLean incorporated the prefrontal/orbitofrontal cortex, septum, amygdalae, and anterior temporal lobes into the limbic system. Over the past few years, diffusion-weighted tractography techniques revealed additional limbic fiber connectivity, which incorporates multiple circuits to the already known complex limbic network. In the current review, we aimed to comprehensively summarize the anatomy of the limbic system and elaborate on the anatomical connectivity of the limbic circuits based on the published literature as an update to the original Papez circuit.

Radiologic-pathologic evidence of brain injury: hypoperfusion in the Papez circuit results in poor neurodevelopmental outcomes in neonatal hypoxic ischemic encephalopathy.

PURPOSE: To provide radiologic-pathologic correlation of brain injury in the Papez circuit in hypoxic-ischemic encephalopathy (HIE) neonates and correlate radiologic findings with long-term neurodevelopmental outcomes. METHODS: Twenty full-term HIE neonates were evaluated. Cerebral blood flow (CBF) values, obtained through pulsed arterial spin labeling (ASL) perfusion-weighted MRI, were compared by permutation test to identify brain regions with statistically significant perfusion changes between 14 HIE neonates without evidence of developmental delay by Bayley-III (mean age 8.2 ± 7.2 days) and 6 HIE neonates with evidence of developmental delay (mean age 13.1 ± 8.0 days). Four histopathologic studies on specimens were taken from post-mortem brains of another group of infants (mean age 10 ± 6.8 days) with HIE. The infants were not the same ones who had MRIs. RESULTS: Significantly decreased perfusion in Papez circuit was found in HIE neonates with developmental delay compared with HIE neonates without delay. Decreased ASL perfusion values were seen in Papez circuit structures of the fornix (p = 0.002), entorhinal cortex (p = 0.048), amygdala (p = 0.036), hippocampus (p = 0.033), and thalamus (p = 0.036). In autopsy specimens of neonates with HIE, anoxic (eosinophilic) neurons, reactive astrocytes, and white matter rarefaction were observed in these regions, providing pathology correlation to the imaging findings of HIE. CONCLUSION: The Papez circuit is susceptible to hypoxic-ischemic injury in neonates as demonstrated by perfusion-weighted imaging and histopathology. This sheds new light onto a possible non-familial mechanism of neuropsychiatric disease evolution initiated in the infant period and raises the potential for early identification of at-risk children.

Postnatal Expression Patterns of Estrogen Receptor Subtypes and Choline Acetyltransferase in Different Regions of the Papez Circuit.

The Papez circuit is crucial for several brain functions, including long-term memory and emotion. Estradiol modulates cognitive functions based on the expression pattern of its receptor subtypes including estrogen receptor (ER) α, ß, and G protein-coupled receptor 30 (GPR30). Similarly, the activity in the cholinergic system correlates with several brain functions, such as learning and memory. In this study, we used immunofluorescence to examine the expression patterns of ERß and Western blotting to analyze GPR30 and choline acetyltransferase (ChAT) expression, in different regions of the Papez circuit, including the prefrontal cortex, hippocampus, hypothalamus, anterior nucleus of the thalamus, and cingulum in female rats at postnatal days (PND) 1, 10, and 56. Our main finding was that the highest expression of ERß and GPR30 was noted in each brain area of the Papez circuit in the PND1 rats, whereas the expression of ChAT was the highest in PND10 rats. These results provide vital information on the postnatal expression patterns of ER subtypes and ChAT in different regions of the Papez circuit.

The goblet sign in the amnestic syndrome of the subcallosal artery infarct.

We here describe an acute-onset amnesic syndrome with evidence of an embolic infarction in the distribution of the subcallosal artery, a proximal branch of the anterior communicating artery. The infarction involved the corpus callosum genu and both fornices, giving a peculiar image on MRI that resembled a goblet. Although infrequent, the subcallosal artery infarction should be considered in the differential diagnosis of patients with an acute amnestic syndrome. We propose "the goblet sign" for the peculiar diffusion-weighted MRI image of the brain in this syndrome.

Newly observed anterior thalamocortical fiber of the thalamus using 7.0T super-resolution magnetic resonance tractography and its implications for the classical Papez circuit.

Here, we have employed recently developed super-resolution tractography using 7.0T-MRI to analyze the fine structures involved in thalamocortical connections, something that has proved difficult using conventional techniques. We detail a newly observed thalamocortical pathway connecting the anterior nucleus of the thalamus and the cingulate cortex not via the internal capsule but via the septal area. The observed pathway is believed to be a classical pathway of the Papez circuit but had not been previously identified.

Environmental Anchoring of Head Direction in a Computational Model of Retrosplenial Cortex.

Allocentric (world-centered) spatial codes driven by path integration accumulate error unless reset by environmental sensory inputs that are necessarily egocentric (body-centered). Previous models of the head direction system avoided the necessary transformation between egocentric and allocentric reference frames by placing visual cues at infinity. Here we present a model of head direction coding that copes with exclusively proximal cues by making use of a conjunctive representation of head direction and location in retrosplenial cortex. Egocentric landmark bearing of proximal cues, which changes with location, is mapped onto this retrosplenial representation. The model avoids distortions due to parallax, which occur in simple models when a single proximal cue card is used, and can also accommodate multiple cues, suggesting how it can generalize to arbitrary sensory environments. It provides a functional account of the anatomical distribution of head direction cells along Papez' circuit, of place-by-direction coding in retrosplenial cortex, the anatomical connection from the anterior thalamic nuclei to retrosplenial cortex, and the involvement of retrosplenial cortex in navigation. In addition to parallax correction, the same mechanism allows for continuity of head direction coding between connected environments, and shows how a head direction representation can be stabilized by a single within arena cue. We also make predictions for drift during exploration of a new environment, the effects of hippocampal lesions on retrosplenial cells, and on head direction coding in differently shaped environments. SIGNIFICANCE STATEMENT: The activity of head direction cells signals the direction of an animal's head relative to landmarks in the world. Although driven by internal estimates of head movements, head direction cells must be kept aligned to the external world by sensory inputs, which arrive in the reference frame of the sensory receptors. We present a computational model, which proposes that sensory inputs are correctly associated to head directions by virtue of a conjunctive representation of place and head directions in the retrosplenial cortex. The model allows for a stable head direction signal, even when the sensory input from nearby cues changes dramatically whenever the animal moves to a different location, and enables stable representations of head direction across connected environments.

Integrity of white matter microstructure in alcoholics with and without Korsakoff's syndrome.

Alcohol dependence results in two different clinical forms: "uncomplicated" alcoholism (UA) and Korsakoff's syndrome (KS). Certain brain networks are especially affected in UA and KS: the frontocerebellar circuit (FCC) and the Papez circuit (PC). Our aims were (1) to describe the profile of white matter (WM) microstructure in FCC and PC in the two clinical forms, (2) to identify those UA patients at risk of developing KS using their WM microstructural integrity as a biomarker. Tract-based spatial statistics and nonparametric voxel-based permutation tests were used to compare diffusion tensor imaging (DTI) data in 7 KS, 20 UA, and 14 healthy controls. The two patient groups were also pooled together and compared to controls. k-means classifications were then performed on mean fractional anisotropy values of significant clusters across all subjects for two fiber tracts from the FCC (the middle cerebellar peduncle and superior cerebellar peduncle) and two tracts from the PC (fornix and cingulum). We found graded effects of WM microstructural abnormalities in the PC of UA and KS. UA patients classified at risk of developing KS using fiber tracts of the PC from DTI data also had the lowest scores of episodic memory. That finding suggests that WM microstructure could be used as a biomarker for early detection of UA patients at risk of developing KS.

Beyond the temporal pole: limbic memory circuit in the semantic variant of primary progressive aphasia.

Despite accruing evidence for relative preservation of episodic memory in the semantic variant of primary progressive aphasia (previously semantic dementia), the neural basis for this remains unclear, particularly in light of their well-established hippocampal involvement. We recently investigated the Papez network of memory structures across pathological subtypes of behavioural variant frontotemporal dementia and demonstrated severe degeneration of all relay nodes, with the anterior thalamus in particular emerging as crucial for intact episodic memory. The present study investigated the status of key components of Papez circuit (hippocampus, mammillary bodies, anterior thalamus, cingulate cortex) and anterior temporal cortex using volumetric and quantitative cell counting methods in pathologically-confirmed cases with semantic variant of primary progressive aphasia (n = 8; 61-83 years; three males), behavioural variant frontotemporal dementia with TDP pathology (n = 9; 53-82 years; six males) and healthy controls (n = 8, 50-86 years; four males). Behavioural variant frontotemporal dementia cases with TDP pathology were selected because of the association between the semantic variant of primary progressive aphasia and TDP pathology. Our findings revealed that the semantic variant of primary progressive aphasia and behavioural variant frontotemporal dementia show similar degrees of anterior thalamic atrophy. The mammillary bodies and hippocampal body and tail were preserved in the semantic variant of primary progressive aphasia but were significantly atrophic in behavioural variant frontotemporal dementia. Importantly, atrophy in the anterior thalamus and mild progressive atrophy in the body of the hippocampus emerged as the main memory circuit regions correlated with increasing dementia severity in the semantic variant of primary progressive aphasia. Quantitation of neuronal populations in the cingulate cortices confirmed the selective loss of anterior cingulate von Economo neurons in behavioural variant frontotemporal dementia. We also show that by end-stage these neurons selectively degenerate in the semantic variant of primary progressive aphasia with preservation of neurons in the posterior cingulate cortex. Overall, our findings demonstrate for the first time, severe atrophy, although not necessarily neuronal loss, across all relay nodes of Papez circuit with the exception of the mammillary bodies and hippocampal body and tail in the semantic variant of primary progressive aphasia. Despite the longer disease course in the semantic variant of primary progressive aphasia compared with behavioural variant frontotemporal dementia, we suggest here that the neural preservation of crucial memory relays (hippocampal→mammillary bodies and posterior cingulate→hippocampus) likely reflects the conservation of specific episodic memory components observed in most patients with semantic variant of primary progressive aphasia.

Targeting papez circuit for cognitive dysfunction- insights into deep brain stimulation for Alzheimer's disease.

Hippocampus is the most widely studied brain area coupled with impairment of memory in a variety of neurological diseases and Alzheimer's disease (AD). The limbic structures within the Papez circuit have been linked to various aspects of cognition. Unfortunately, the brain regions that include this memory circuit are often ignored in terms of understanding cognitive decline in these diseases. To properly comprehend where cognition problems originate, it is crucial to clarify any aberrant contributions from all components of a specific circuit -on both a local and a global level. The pharmacological treatments currently available are not long lasting. Deep Brain Stimulation (DBS) emerged as a new powerful therapeutic approach for alleviation of the cognitive dysfunctions. Metabolic, functional, electrophysiological, and imaging studies helped to find out the crucial nodes that can be accessible for DBS. Targeting these nodes within the memory circuit produced significant improvement in learning and memory by disrupting abnormal circuit activity and restoring the physiological network. Here, we provide an overview of the neuroanatomy of the circuit of Papez along with the mechanisms and various deep brain stimulation targets of the circuit structures which could be significant for improving cognitive dysfunctions in AD.

Is the Papez circuit the location of the elusive episodic memory engram?

All of the brain structures and white matter that make up Papez' circuit, as well as the circuit as a whole, are implicated in the literature in episodic memory formation and recall. This paper shows that Papez' circuit has the detailed structure and connectivity that is evidently required to support the episodic memory engram, and that identifying Papez' circuit as the location of the engram answers a number of long-standing questions regarding the role of medial temporal lobe structures in episodic memory. The paper then shows that the process by which the episodic memory engram may be formed is a network-wide Hebbian potentiation termed "racetrack potentiation", whose frequency corresponds to that observed in vivo in humans for memory functions. Further, by considering the microcircuits observed in the medial temporal lobe structures forming Papez' circuit, the paper establishes the neural mechanisms behind the required functions of sensory information storage and recall, pattern completion, pattern separation, and memory consolidation. The paper shows that Papez' circuit has the necessary connectivity to gather the various elements of an episodic memory occurring within Pöppel's experienced time or "quantum of experience". Finally, the paper shows how the memory engram located in Papez' circuit might be central to the formation of a duplicate engram in the cortex enabling consolidation and long-term storage of episodic memories.

Age dependent path integration deficit in 5xFAD mice.

Alzheimer's disease (AD) is a severe neurodegenerative disorder and the most common form of dementia in elderly individuals, characterized by memory deficits, cognitive decline, and neuropathology. The identification of preclinical markers for AD remains elusive. We employed an ultrasound-evoked spatial memory assay to investigate path integration (PI) in wild type C57BL/6 J and 5xFAD mice. We observed significant recruitment of the mammillary bodies (MB) and subiculum (Sub) - core regions of the Papez circuit during PI, as indicated by increased expression of the immediate early gene c-Fos in C57BL/6 J mice. In 5xFAD mice, amyloid-beta (Aß) vulnerability in the MB and Sub was evident at 3-months of age, preceding widespread pathology at 5-months of age. In parallel, we detected significant behavioral deficits in PI in the 5XFAD mice at 5- but not 3-months of age. Sex based analysis revealed a more profound deficit in males compared to females at 5-months of age. Our data suggest PI may be as an early indicator of AD, potentially associated with dysfunction within the Papez circuit.

Abnormal white matter integrity in Papez circuit in first-episode medication-naive adults with anxious depression: A combined voxel-based analysis and region of interest study.

BACKGROUND: Anxious depression is one of the subtypes of major depressive disorder (MDD), usually defined as "patients with MDD and high levels of anxiety symptoms". Compared to non-anxious MDD (naMDD), patients with anxious MDD (aMDD) have more severe depressive symptoms and suicidal ideation, worse treatment outcomes and remission rates, and poorer prognosis. Current research suggests that the Papez circuit is an important brain structure closely related to emotion, memory, and cognition. This study applied DTI to explore the altered white matter integrity in Papez circuit of patients with aMDD. METHODS: DTI data were acquired from 30 medication-naive outpatients with naMDD and 55 with aMDD and 88 demographically similar healthy control (HC) subjects. Voxel-based analysis (VBM) and region of interest (ROI) analysis were conducted to explore the significant difference of fractional anisotropy (FA) values among 3 groups. Pearson's correlations were performed to analyze the correlation between FA values and the score of HAMA-14 and HAMD-17. RESULTS: We found that aMDD patients had significantly higher FA values in left fornix (belong to Papez circuit) and left posterior thalamic radiation and right anterior corona radiata (belong to limbic-thalamo-cortical circuitry) compared with HC. And there was variability in the white matter integrity in right posterior thalamic radiation (belong to limbic-thalamo-cortical circuitry) and left fornix (belong to Papez circuit) between aMDD and naMDD patients. LIMITATIONS: The cross-sectional study and the population vary between aMDD group and naMDD group are limitations. CONCLUSIONS: Abnormal white matter integrity in Papez circuit and Limbic-Thalamo-Cortical circuitry may play an important role in the neuropathology of aMDD and might help to identify aMDD.

A case of germinoma located in the fornix inducing transsynaptic atrophy of the Papez circuit.

Germinoma is a rare CNS germ cell tumor preferentially affecting children and young adults. Intracranial germinomas arise typically in the neurohypophysis and pineal region and occasionally in the basal ganglia and thalamus. Germinomas in the basal ganglia and thalamus are characterized by the ipsilateral cerebral and brainstem hemiatrophy with slowly progressive neurological deficits, which is due to tumor infiltration into the thalamocortical and corticospinal tract and induction of anterograde and retrograde Wallerian degeneration. We report an 11-year-old boy with a mass located in the fornix incidentally discovered on the first work-up of his minor head injury. Imaging findings revealed the ipsilateral atrophy of the mammillary body and the fornix. Stereotactic brain biopsy was performed and the final diagnosis was germinoma. The ipsilateral atrophy of the mammillary body and the fornix implied the transsynaptic degeneration via the Papez circuit. We discuss the unique nature of germinomas and underlying pathological mechanisms.

Effects of (-)-MBP, a novel 5-HT2C agonist and 5-HT2A/2B antagonist/inverse agonist on brain activity: A phMRI study on awake mice.

A novel serotonin ligand (-)-MBP was developed for the treatment of schizophrenia that has 5-HT2A/2B antagonist activity together with 5-HT2C agonist activity. The multi-functional activity of this novel drug candidate was characterized using pharmacological magnetic resonance imaging. It was hypothesized (-)-MBP would affect activity in brain areas associated with sensory perception. Adult male mice were given one of three doses of (-)-MBP (3.0, 10, 18 mg/kg) or vehicle while fully awake during the MRI scanning session and imaged for 15 min post I.P. injection. BOLD functional imaging was used to follow changes in global brain activity. Data for each treatment were registered to a 3D MRI mouse brain atlas providing site-specific information on 132 different brain areas. There was a dose-dependent decrease in positive BOLD signal in numerous brain regions, especially thalamus, cerebrum, and limbic cortex. The 3.0 mg/kg dose had the greatest effect on positive BOLD while the 18 mg/kg dose was less effective. Conversely, the 18 mg/kg dose showed the greatest negative BOLD response while the 3.0 mg/kg showed the least. The prominent activation of the thalamus and cerebrum included the neural circuitry associated with Papez circuit of emotional experience. When compared to vehicle, the 3.0 mg dose affected all sensory modalities, for example, olfactory, somatosensory, motor, and auditory except for the visual cortex. These findings show that (-)-MBP, a ligand with both 5-HT2A/2B antagonist and 5-HT2C agonist activities, interacts with thalamocortical circuitry and impacts areas involved in sensory perception.

Monoamine Oxidase: A Potential Link in Papez circuit to Generalized Anxiety Disorders.

Anxiety is a common mental illness that affects a large number of people around the world, and its treatment is often based on the use of pharmacological substances such as benzodiazepines, serotonin, and 5-hydroxytyrosine (MAO) neurotransmitters. MAO neurotransmitters levels are deciding factors in the biological effects. This review summarizes the current understanding of the MAO system and its role in the modulation of anxiety-related brain circuits and behavior. The MAO-A polymorphisms have been implicated in the susceptibility to generalized anxiety disorder (GAD) in several investigations. The 5-HT system is involved in a wide range of physiological and behavioral processes, involving anxiety, aggressiveness, stress reactions, and other elements of emotional intensity. Among these, 5-HT, NA, and DA are the traditional 5-HT neurons that govern a range of biological activities, including sleep, alertness, eating, thermoregulation, pains, emotion, and memory, as anticipated considering their broad projection distribution in distinct brain locations. The DNMTs (DNA methyltransferase) protein family, which increasingly leads a prominent role in epigenetics, is connected with lower transcriptional activity and activates DNA methylation. In this paper, we provide an overview of the current state of the art in the elucidation of the brain's complex functions in the regulation of anxiety.

Injury to the circuit of Papez: An overlooked cause of recurrent seizures.

Key Clinical Message: Papez' circuit is a unique neural pathway in the limbic system that is correlated with seizure activity. Injuries affecting Papez' circuit are often small and unusual in location but can be identifiable in MRI and functional imaging modalities, which can be helpful in the workup of refractory epilepsy. Abstract: The Papez circuit is a unique neural pathway in the limbic system of the brain. We review a patient presenting with recurrent seizures as the main manifestation of Papez' circuit pathology. The radiologic features of ischemia involving the mammillothalamic tract in Papez' circuit were correlated with the seizure activity.