Distinct Brain Areas Research Articles

Creation of Neuronal Ensembles and Cell-Specific Homeostatic Plasticity through Chronic Sparse Optogenetic Stimulation.

Cortical computations emerge from the dynamics of neurons embedded in complex cortical circuits. Within these circuits, neuronal ensembles, which represent subnetworks with shared functional connectivity, emerge in an experience-dependent manner. Here we induced ensembles in ex vivo cortical circuits from mice of either sex by differentially activating subpopulations through chronic optogenetic stimulation. We observed a decrease in voltage correlation, and importantly a synaptic decoupling between the stimulated and nonstimulated populations. We also observed a decrease in firing rate during Up-states in the stimulated population. These ensemble-specific changes were accompanied by decreases in intrinsic excitability in the stimulated population, and a decrease in connectivity between stimulated and nonstimulated pyramidal neurons. By incorporating the empirically observed changes in intrinsic excitability and connectivity into a spiking neural network model, we were able to demonstrate that changes in both intrinsic excitability and connectivity accounted for the decreased firing rate, but only changes in connectivity accounted for the observed decorrelation. Our findings help ascertain the mechanisms underlying the ability of chronic patterned stimulation to create ensembles within cortical circuits and, importantly, show that while Up-states are a global network-wide phenomenon, functionally distinct ensembles can preserve their identity during Up-states through differential firing rates and correlations.SIGNIFICANCE STATEMENT The connectivity and activity patterns of local cortical circuits are shaped by experience. This experience-dependent reorganization of cortical circuits is driven by complex interactions between different local learning rules, external input, and reciprocal feedback between many distinct brain areas. Here we used an ex vivo approach to demonstrate how simple forms of chronic external stimulation can shape local cortical circuits in terms of their correlated activity and functional connectivity. The absence of feedback between different brain areas and full control of external input allowed for a tractable system to study the underlying mechanisms and development of a computational model. Results show that differential stimulation of subpopulations of neurons significantly reshapes cortical circuits and forms subnetworks referred to as neuronal ensembles.

Population burst propagation across interacting areas of the brain.

For many perceptual and behavioral tasks, a prominent feature of neural spike trains involves high firing rates across relatively short intervals of time. We call these events "population bursts." Because during a population burst information is, presumably, transmitted from one part of the brain to another, burst timing should reveal activity related to the flow of information across neural circuits. We developed a statistical method (based on a point process model) of determining, accurately, the time of the maximum (peak) population firing rate on a trial-by-trial basis and used it to characterize burst propagation across areas. We then examined the tendency of peak firing rates in distinct brain areas to shift earlier or later in time, together, across repeated trials, and found this trial-to-trial coupling of peak times to be a sensitive indicator of interaction across populations. In the data we examined, from the Allen Brain Observatory, we found many very strong correlations (95% confidence intervals above 0.75) in cases where standard methods were unable to demonstrate cross-area correlation. The statistical model introduced cross-area covariation only through population-level trial-dependent time shifts and gain constants (values of which were learned from the data), yet it provided very good fits to data histograms, including histograms of spike count correlations within and across visual areas. Our results demonstrate the utility of carefully assessing timing and propagation, across brain regions, of transient bursts in neural population activity, based on multiple spike train recordings.NEW & NOTEWORTHY We developed a novel statistical method for identifying coordinated propagation of activity across populations of spiking neurons, with high temporal accuracy. Using simultaneous recordings from three visual areas we document precise timing relationships on a trial-by-trial basis, and we show how previously existing techniques can fail to discover coordinated activity in cases where the new approach finds very strong cross-area correlation.

Radiosynthesis and Preclinical Evaluation of an 18F-Labeled Triazolopyridopyrazine-Based Inhibitor for Neuroimaging of the Phosphodiesterase 2A (PDE2A).

The cyclic nucleotide phosphodiesterase 2A is an intracellular enzyme which hydrolyzes the secondary messengers cAMP and cGMP and therefore plays an important role in signaling cascades. A high expression in distinct brain areas as well as in cancer cells makes PDE2A an interesting therapeutic and diagnostic target for neurodegenerative and neuropsychiatric diseases as well as for cancer. Aiming at specific imaging of this enzyme in the brain with positron emission tomography (PET), a new triazolopyridopyrazine-based derivative (11) was identified as a potent PDE2A inhibitor (IC50, PDE2A = 1.99 nM; IC50, PDE10A ~2000 nM) and has been radiofluorinated for biological evaluation. In vitro autoradiographic studies revealed that [18F]11 binds with high affinity and excellent specificity towards PDE2A in the rat brain. For the PDE2A-rich region nucleus caudate and putamen an apparent KD value of 0.24 nM and an apparent Bmax value of 16 pmol/mg protein were estimated. In vivo PET-MR studies in rats showed a moderate brain uptake of [18F]11 with a highest standardized uptake value (SUV) of 0.97. However, no considerable enrichment in PDE2A-specific regions in comparison to a reference region was detectable (SUVcaudate putamen = 0.51 vs. SUVcerebellum = 0.40 at 15 min p.i.). Furthermore, metabolism studies revealed a considerable uptake of radiometabolites of [18F]11 in the brain (66% parent fraction at 30 min p.i.). Altogether, despite the low specificity and the blood–brain barrier crossing of radiometabolites observed in vivo, [18F]11 is a valuable imaging probe for the in vitro investigation of PDE2A in the brain and has potential as a lead compound for further development of a PDE2A-specific PET ligand for neuroimaging.

Korsakoff syndrome and altered pain perception: a search of underlying neural mechanisms.

Patients with Korsakoff syndrome (KS) may have a diminished pain perception. Information on KS and pain is scarce and limited to case descriptions. The present study is the first to investigate the underlying neural mechanisms of altered pain perception in patients with KS more systematically. We conducted a literature search on neural correlates of pain perception in other neurocognitive disorders in which extensive research was done. The brain areas that are affected in KS showed considerable overlap with the neural correlates of pain perception in other neurocognitive disorders. We discussed which different aspects of disturbed pain perception could play a role within KS, based on distinct neural damage and brain areas involved in pain perception. Combining current knowledge, we hypothesize that diminished pain perception in KS may be related to lesioned neural connections between cerebral cortical networks and relays of mainly the thalamus, the periaqueductal gray, and possibly lower brain stem regions projecting to the cerebellum. Based on these neural correlates of altered pain perception, we assume that increased pain thresholds, inhibition of pain signals, and disturbed input to cerebral and cerebellar cortical areas involved in pain processing, all are candidate mechanisms in cases of diminished pain perception in KS. We recommend that clinicians need to be alert for somatic morbidity in patients with KS. Due to altered neural processing of nociceptive input the clinical symptoms of somatic morbidity may present differently (i.e. limited pain responses) and therefore are at risk of being missed.

RNeuMark: A Riemannian EEG Analysis Framework for Neuromarketing

Neuromarketing exploits neuroimaging techniques so as to reinforce the predictive power of conventional marketing tools, like questionnaires and focus groups. Electroencephalography (EEG) is the most commonly encountered neuroimaging technique due to its non-invasiveness, low-cost, and its very recent embedding in wearable devices. The transcription of brainwave patterns to consumer attitude is supported by various signal descriptors, while the quest for profitable novel ways is still an open research question. Here, we suggest the use of sample covariance matrices as alternative descriptors, that encapsulate the coordinated neural activity from distinct brain areas, and the adoption of Riemannian geometry for their handling. We first establish the suitability of Riemannian approach for neuromarketing-related problems and then suggest a relevant decoding scheme for predicting consumers’ choices (e.g., willing to buy or not a specific product). Since the decision-making process involves the concurrent interaction of various cognitive processes and consequently of distinct brain rhythms, the proposed decoder takes the form of an ensemble classifier that builds upon a multi-view perspective, with each view dedicated to a specific frequency band. Adopting a standard machine learning procedure, and using a set of trials (training data) in conjunction with the associated behavior labels (“buy”/ “not buy”), we train a battery of classifiers accordingly. Each classifier is designed to operate in the space recovered from the inter-trial distances of SCMs and to cast a rhythm-depended decision that is eventually combined with the predictions of the rest ones. The demonstration and evaluation of the proposed approach are performed in 2 neuromarketing-related datasets of different nature. The first is employed to showcase the potential of the suggested descriptor, while the second to showcase the decoder’s superiority against popular alternatives in the field.

A whole-brain 3D myeloarchitectonic atlas: Mapping the Vogt-Vogt legacy to the cortical surface

Building precise and detailed parcellations of anatomically and functionally distinct brain areas has been a major focus in Neuroscience. Pioneer anatomists parcellated the cortical manifold based on extensive histological studies of post-mortem brain, harnessing local variations in cortical cyto- and myeloarchitecture to define areal boundaries. Compared to the cytoarchitectonic field, where multiple neuroimaging studies have recently translated this old legacy data into useful analytical resources, myeloarchitectonics, which parcellate the cortex based on the organization of myelinated fibers, has received less attention. Here, we present the neocortical surface-based myeloarchitectonic atlas based on the histology-derived maps of the Vogt-Vogt school and its 2D translation by Nieuwenhuys. In addition to a myeloarchitectonic parcellation, our package includes intracortical laminar profiles of myelin content based on Vogt-Vogt-Hopf original publications. Histology-derived myelin density mapped on our atlas demonstrated a close overlap with in vivo quantitative MRI markers for myelin and relates to cytoarchitectural features. Complementing the existing battery of approaches for digital cartography, the whole-brain myeloarchitectonic atlas offers an opportunity to validate imaging surrogate markers of myelin in both health and disease.

A functional magnetic resonance imaging examination of audiovisual observation of a point-light string quartet using intersubject correlation and physical feature analysis.

We use functional Magnetic Resonance Imaging (fMRI) to explore synchronized neural responses between observers of audiovisual presentation of a string quartet performance during free viewing. Audio presentation was accompanied by visual presentation of the string quartet as stick figures observed from a static viewpoint. Brain data from 18 musical novices were obtained during audiovisual presentation of a 116 s performance of the allegro of String Quartet, No. 14 in D minor by Schubert played by the ‘Quartetto di Cremona.’ These data were analyzed using intersubject correlation (ISC). Results showed extensive ISC in auditory and visual areas as well as parietal cortex, frontal cortex and subcortical areas including the medial geniculate and basal ganglia (putamen). These results from a single fixed viewpoint of multiple musicians are greater than previous reports of ISC from unstructured group activity but are broadly consistent with related research that used ISC to explore listening to music or watching solo dance. A feature analysis examining the relationship between brain activity and physical features of the auditory and visual signals yielded findings of a large proportion of activity related to auditory and visual processing, particularly in the superior temporal gyrus (STG) as well as midbrain areas. Motor areas were also involved, potentially as a result of watching motion from the stick figure display of musicians in the string quartet. These results reveal involvement of areas such as the putamen in processing complex musical performance and highlight the potential of using brief naturalistic stimuli to localize distinct brain areas and elucidate potential mechanisms underlying multisensory integration.

Exploration of abnormal dynamic spontaneous brain activity in patients with high myopia via dynamic regional homogeneity analysis.

AimPatients with high myopia (HM) reportedly exhibit changes in functional brain activity, but the mechanism underlying such changes is unclear. This study was conducted to observe differences in dynamic spontaneous brain activity between patients with HM and healthy controls (HCs) via dynamic regional homogeneity (dReHo) analysis.MethodsResting-state functional magnetic resonance imaging (rs-fMRI) scans were performed on 82 patients with HM and 59 HCs who were closely matched for age, sex, and weight. The dReHo approach was used to assess local dynamic activity in the human brain. The association between mean dReHo signal values and clinical symptoms in distinct brain areas in patients with HM was determined via correlation analysis.ResultsIn the left fusiform gyrus (L-FG), right inferior temporal gyrus (R-ITG), right Rolandic operculum (R-ROL), right postcentral gyrus (R-PoCG), and right precentral gyrus (R-PreCG), dReHo values were significantly greater in patients with HM than in HCs.ConclusionPatients with HM have distinct functional changes in various brain regions that mainly include the L-FG, R-ITG, R-ROL, R-PoCG, and R-PreCG. These findings constitute important evidence for the roles of brain networks in the pathophysiological mechanisms of HM and may aid in the diagnosis of HM.

Superior control of inflammatory pain by corticotropin-releasing factor receptor 1 via opioid peptides in distinct pain-relevant brain areas

BackgroundUnder inflammatory conditions, the activation of corticotropin-releasing factor (CRF) receptor has been shown to inhibit pain through opioid peptide release from immune cells or neurons. CRF’s effects on human and animal pain modulation depend, however, on the distribution of its receptor subtypes 1 and 2 (CRF-R1 and CRF-R2) along the neuraxis of pain transmission. The objective of this study is to investigate the respective role of each CRF receptor subtype on centrally administered CRF-induced antinociception during inflammatory pain.MethodsThe present study investigated the role of intracerebroventricular (i.c.v.) CRF receptor agonists on nociception and the contribution of cerebral CRF-R1 and/or CRF-R2 subtypes in an animal model of Freund’s complete adjuvant (FCA)-induced hind paw inflammation. Methods used included behavioral experiments, immunofluorescence confocal analysis, and reverse transcriptase-polymerase chain reaction.ResultsIntracerebroventricular, but systemically inactive, doses of CRF elicited potent, dose-dependent antinociceptive effects in inflammatory pain which were significantly antagonized by i.c.v. CRF-R1-selective antagonist NBI 27914 (by approximately 60%) but less by CRF-R2-selective antagonist K41498 (by only 20%). In line with these findings, i.c.v. administration of CRF-R1 agonist stressin I produced superior control of inflammatory pain over CRF-R2 agonist urocortin-2. Intriguingly, i.c.v. opioid antagonist naloxone significantly reversed the CRF as well as CRF-R1 agonist-elicited pain inhibition. Consistent with existing evidence of high CRF concentrations in brain areas such as the thalamus, hypothalamus, locus coeruleus, and periaqueductal gray following its i.c.v. administration, double-immunofluorescence confocal microscopy demonstrated primarily CRF-R1-positive neurons that expressed opioid peptides in these pain-relevant brain areas. Finally, PCR analysis confirmed the predominant expression of the CRF-R1 over CRF-R2 in representative brain areas such as the hypothalamus.ConclusionTaken together, these findings suggest that CRF-R1 in opioid-peptide-containing brain areas plays an important role in the modulation of inflammatory pain and may be a useful therapeutic target for inflammatory pain control.

Cross-frequency coupling of frontal theta and posterior alpha is unrelated to the fidelity of visual long-term memory encoding

ABSTRACT Because visual long-term memory relies on multiple spatially distinct brain areas, encoding representations is likely to rely on networks formed via large-scale coupled neuronal oscillations. Decreases in occipital alpha power and increases in mid-frontal theta power appear to individually contribute to the encoding of visual long-term memories. Here we ask whether these oscillations form a coupled network. We show that neither amplitude-amplitude nor phase-amplitude coupling between frontal theta and posterior alpha are related to observers' subsequent memory. Correlations between alpha and theta power were stronger during eyes-open, resting-state periods than immediately following the presentation of a to-be-remembered picture. Finally, we found that the strength of theta-alpha coupling was not modified by temporal lobe anodal transcranial direct current stimulation, despite performance showing enhanced memory. These findings indicate that posterior alpha and frontal theta activity are not simply component parts of a larger scale coupled network underlying visual memory.

Role of the thyrotropin-releasing hormone of the limbic system in mood and eating regulation.

Thyrotropin-releasing hormone (TRH) and its receptors are expressed in the hypothalamus and limbic regions. Brain thyrotropin-releasing hormone actions are exerted directly through its receptors and indirectly by modulating the effects of neurotransmitters such as glutamate, gamma-aminobutyric acid, acetylcholine, and dopamine. The thyrotropin-releasing hormone has been implicated in eating and mood regulation. We integrate studies that analyze the role of limbic thyrotropin-releasing hormone on displaying depressive- and anxiety-like behaviors and anorexia or hyperphagia. Since the decade of 1970s, different efforts have been made to identify some of the thyrotropin-releasing hormone effects and its analogs in feeding regulation or to ameliorate symptoms in patients diagnosed with mood disorders, and to correlate anxious or depressive parameters with thyrotropin-releasing hormone levels in the cerebrospinal fluid or its expression in postmortem brain areas of affected patients. Pharmacological studies where the thyrotropin-releasing hormone is administered to animals by different routes and to distinct brain areas have elucidated its actions in behavioral changes of mood and feeding parameters. In addition, a variety of animal models of depression, anxiety, or anorexia and hyperphagia has suggested the association between the hypothalamic and limbic TRHergic system and the regulation of mood and feeding alterations. Different approaches employ the administration of anti-depressant, anxiolytic or anorectic agents to animals and describe changes in thyrotropin-releasing hormone content or expression in hypothalamic or limbic regions. The different effects on mood that result from modulating thyrotropin-releasing hormone expression may be beneficial to treat patients diagnosed with eating disorders.

Network-specific differences in transient brain activity at rest are associated with age-related reductions in motor performance

Multiple functional changes occur in the brain with increasing age. Among those, older adults typically display more restricted fluctuations of brain activity, both during resting-state and task execution. These altered dynamic patterns have been linked to reduced task performance across multiple behavioral domains. Windowed functional connectivity, which is typically employed in the study of connectivity dynamics, however, might not be able to properly characterize moment-to-moment variations of individual networks. In the present study, we used innovation-driven co-activation patterns (ICAP) to overcome this limitation and investigate the length (duration) and frequency (innovation) in which various brain networks emerged across the adult lifespan (N= 92) during a resting-state period. We identified a link between increasing age and a tendency to engage brain areas with distinct functional associations simultaneously as a single network. The emergence of isolated and spatially well-defined visual, motor, frontoparietal, and posterior networks decreased with increased age. This reduction in dynamics of specialized networks mediated age-related performance decreases (i.e., increases in interlimb interference) in a bimanual motor task. Altogether, our findings demonstrated that older compared to younger adults tend to activate fewer network configurations, which include multiple functionally distinct brain areas. The reduction in independent emergence of functionally well-defined and task-relevant networks may reflect an expression of brain dedifferentiation and is likely associated with functional modulatory deficits, negatively impacting motor behavior.

Frequency-Specific Blood Oxygen Level Dependent Oscillations Associated With Pain Relief From Ankle Acupuncture in Patients With Chronic Low Back Pain.

Objective: Recent advances in brain imaging have deepened our knowledge of the neural activity in distinct brain areas associated with acupuncture analgesia. However, there has not been conclusive research into the frequency-specific resting-state functional changes associated with acupuncture analgesia in patients with chronic pain. Here, we aimed to characterize changes across multiple frequencies of resting-state cortical activity associated with ankle acupuncture stimulation (AAS) in patients with chronic low back pain (CLBP) and healthy controls.Methods: Twenty seven patients with CLBP and Twenty five age- and gender-matched healthy volunteers were enrolled in the study. Participants received tactile sham acupuncture (TSA) and AAS, respectively. The whole-brain amplitude of low-frequency fluctuation (ALFF) in the range 0.01–0.25 Hz was assessed for changes associated with each intervention. Further, a visual analog scale (VAS) was used to collect subjective measures of pain intensity in patients. Linear mixed-effect modeling (LME) was used to examine the mean ALFF values of AAS and TSA between patients and healthy controls.Results: The ALFF was modulated in the default mode network (an increase in the medial prefrontal cortex, and a decrease in the cerebellum/posterior ingulate/parahippocampus, P < 0.01, corrected) in both patients and controls. Decreased ALFF in the bilateral insular was frequency-dependent. Modulations in the cerebellum and right insular were significantly correlated with VAS pain score after AAS (P < 0.01).Conclusion: Hence, frequency-specific resting-state activity in the cerebellum and insular was correlated to AAS analgesia. Our frequency-specific analysis of ALFF may provide novel insights related to pain relief from acupuncture.

The Effect of Valproic Acid Exposure throughout Development on Microglia Number in the Prefrontal Cortex, Hippocampus and Cerebellum

Microglia serve as resident immune cells in the brain, responding to insults and pathological developments. They have also been implicated in shaping synaptic development and regulation. The present study examined microglial cell density in a number of brain regions across select postnatal (P) ages along with the effects of valproic acid (VPA) on microglia density. Specifically, C57BL/6JCx3CR1+/GFP mice were examined for microglial cell number changes on P7, P14, P30, and P60 under baseline conditions and following 400 mg/kg VPA or saline. The prefrontal cortex (PFC), hippocampus and cerebellum were observed. Under control conditions, the results showed a shift in the number of microglia in these brain areas throughout development with a peak density in the hippocampus at P14 and an increase in PFC microglial numbers from P15 to P30. Interestingly, VPA treatment enhanced microglial numbers in a region-specific manner. VPA at P7 increased microglial cell number in the hippocampus and cerebellum whereas P14 VPA treatment altered microglial density in the cerebellum only. Cerebellar increases also occurred after VPA at P30, and were attended by an effect of increased numbers in the PFC. Finally, animals treated with VPA at P60 exhibited decreased microglia density in the hippocampus only. These results suggest rapid VPA-induced increases in microglial cell density in a developmentally-regulated fashion which differs across distinct brain areas. Furthermore, in the context of prior reports that early VPA causes excitotoxic damage, the present findings suggest early VPA exposure may provide a model for studying altered microglial responses to early toxicant challenge.

Striatal oxidative damages and neuroinflammation correlate with progression and survival of Lewy body and Alzheimer diseases.

Neurodegenerative diseases are a class of chronic and complex disorders featuring progressive loss of neurons in distinct brain areas. The mechanisms responsible for the disease progression in neurodegeneration are not fully illustrated. In this observational study, we have examined diverse biochemical parameters in the caudate and putamen of patients with Lewy body diseases (LBDs) and Alzheimer disease (AD), shedding some light on the involvement of oxidative damage and neuroinflammation in advanced neurodegeneration. We performed Spearman and Mantel-Cox analyses to investigate how oxidative stress and neuroinflammation exert comprehensive effects on disease progression and survival. Disease progression in LBDs correlated positively with poly (ADP-Ribose) and triggering receptors expressed on myeloid cell 2 levels in the striatum of LBD cohorts, indicating that potential parthanatos was a dominant feature of worsening disease progression and might contribute to switching microglial inflammatory phenotypes. Disease progression in AD corresponds negatively with 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and myeloperoxidase concentrations in the striatum, suggesting that possible mitochondria dysfunction may be involved in the progression of AD via a mechanism of β-amyloid entering the mitochondria and subsequent free radicals generation. Patients with lower striatal 8-oxo-dG and myeloperoxidase levels had a survival advantage in AD. The age of onset also affected disease progression. Tissue requests for the postmortem biochemistry, genetics, and autoradiography studies were approved by the Washington University Alzheimer's Disease Research Center (ADRC) Biospecimens Committee (ethics approval reference number: T1705, approval date: August 6, 2019). Recombinant DNA and Hazardous Research Materials were approved by the Washington University Environmental Health & Safety Biological Safety Committee (approval code: 3739, approval date: February 25, 2020). Radioactive Material Authorization was approved by the Washington University Environmental Health & Safety Radiation Safety Committee (approval code: 1056, approval date: September 18, 2019).

The Neurotransmitter Receptor Architecture of the Mouse Olfactory System.

The uptake, transmission and processing of sensory olfactory information is modulated by inhibitory and excitatory receptors in the olfactory system. Previous studies have focused on the function of individual receptors in distinct brain areas, but the receptor architecture of the whole system remains unclear. Here, we analyzed the receptor profiles of the whole olfactory system of adult male mice. We examined the distribution patterns of glutamatergic (AMPA, kainate, mGlu2/3, and NMDA), GABAergic (GABAA, GABAA(BZ), and GABAB), dopaminergic (D1/5) and noradrenergic (α1 and α2) neurotransmitter receptors by quantitative in vitro receptor autoradiography combined with an analysis of the cyto- and myelo-architecture. We observed that each subarea of the olfactory system is characterized by individual densities of distinct neurotransmitter receptor types, leading to a region- and layer-specific receptor profile. Thereby, the investigated receptors in the respective areas and strata showed a heterogeneous expression. Generally, we detected high densities of mGlu2/3Rs, GABAA(BZ)Rs and GABABRs. Noradrenergic receptors revealed a highly heterogenic distribution, while the dopaminergic receptor D1/5 displayed low concentrations, except in the olfactory tubercle and the dorsal endopiriform nucleus. The similarities and dissimilarities of the area-specific multireceptor profiles were analyzed by a hierarchical cluster analysis. A three-cluster solution was found that divided the areas into the (1) olfactory relay stations (main and accessory olfactory bulb), (2) the olfactory cortex (anterior olfactory cortex, dorsal peduncular cortex, taenia tecta, piriform cortex, endopiriform nucleus, entorhinal cortex, orbitofrontal cortex) and the (3) olfactory tubercle, constituting its own cluster. The multimodal receptor-architectonic analysis of each component of the olfactory system provides new insights into its neurochemical organization and future possibilities for pharmaceutic targeting.

The Individual Inclination to an Occupation and its Neuronal Correlate

Many young people decide their professional direction during adolescence. This often coincides with vulnerable phases of puberty-related maturation that is usually accompanied by difficulties in assessing one’s personal inclinations and competences. Several psychological tests have been established among teachers and career advisers serving as a tool for professional coaching the teenagers’ competences and preferences. Many tools are based on the “Theory of Vocational Personalities in Work Environment” developed by John L. Holland since the 1950s, comprising the “RIASEC” model. Today, this theory provides the basis for tests which are used and refined all over the world. Professor Stangl’s online assessable “Situational Interest Test” (SIT) is based on Holland’s theory. By means of 30 short assessments the SIT questionnaire assesses the participant’s personality traits: Realistic (“Doers”), Investigative (“Thinkers”), Artistic (“Creators”), Social (“Helpers”), Enterprising (“Persuaders”), and Conventional (“Organizers”). Modern Magnetic Resonance Imaging (MRI) is able to discriminate between the brain’s compartments as Gray and White Matter using Voxel-Based Morphometry (VBM). This tool allows to reshape and to normalize human brains’ structure to statistically examining individual brains. Up to now findings from 20 years of functional MRI gave detailed insights in correlations between brain structures and mental functions. Hence, knowledge on structural base of cognitive or behavioral patterns is available as a brain’s map for assigning anatomical regions to their functions. The present study demonstrates that there are statistically relevant correlations between all dimensions of Holland’s RIASEC theory by assessing individual professional inclinations and the neuronal structures of the brain. Results show correspondence between the personality traits assigned by the RIASEC test and the functions of significant structural alterations in distinct brain areas well-known from literature.

Sign-specific stimulation 'hot' and 'cold' spots in Parkinson's disease validated with machine learning.

Deep brain stimulation of the subthalamic nucleus has become a standard therapy for Parkinson’s disease. Despite extensive experience, however, the precise target of optimal stimulation and the relationship between site of stimulation and alleviation of individual signs remains unclear. We examined whether machine learning could predict the benefits in specific Parkinsonian signs when informed by precise locations of stimulation. We studied 275 Parkinson’s disease patients who underwent subthalamic nucleus deep brain stimulation between 2003 and 2018. We selected pre-deep brain stimulation and best available post-deep brain stimulation scores from motor items of the Unified Parkinson's Disease Rating Scale (UPDRS-III) to discern sign-specific changes attributable to deep brain stimulation. Volumes of tissue activated were computed and weighted by (i) tremor, (ii) rigidity, (iii) bradykinesia and (iv) axial signs changes. Then, sign-specific sites of optimal (‘hot spots’) and suboptimal efficacy (‘cold spots’) were defined. These areas were subsequently validated using machine learning prediction of sign-specific outcomes with in-sample and out-of-sample data (n = 51 subthalamic nucleus deep brain stimulation patients from another institution). Tremor and rigidity hot spots were largely located outside and dorsolateral to the subthalamic nucleus whereas hot spots for bradykinesia and axial signs had larger overlap with the subthalamic nucleus. Using volume of tissue activated overlap with sign-specific hot and cold spots, support vector machine classified patients into quartiles of efficacy with ≥92% accuracy. The accuracy remained high (68–98%) when only considering volume of tissue activated overlap with hot spots but was markedly lower (41–72%) when only using cold spots. The model also performed poorly (44–48%) when using only stimulation voltage, irrespective of stimulation location. Out-of-sample validation accuracy was ≥96% when using volume of tissue activated overlap with the sign-specific hot and cold spots. In two independent datasets, distinct brain areas could predict sign-specific clinical changes in Parkinson’s disease patients with subthalamic nucleus deep brain stimulation. With future prospective validation, these findings could individualize stimulation delivery to optimize quality of life improvement.

Primate extrastriate cortical area MST: a gateway between sensation and cognition.

Primate visual cortex consists of dozens of distinct brain areas, each providing a highly specialized component to the sophisticated task of encoding the incoming sensory information and creating a representation of our visual environment that underlies our perception and action. One such area is the medial superior temporal cortex (MST), a motion-sensitive, direction-selective part of the primate visual cortex. It receives most of its input from the middle temporal (MT) area, but MST cells have larger receptive fields and respond to more complex motion patterns. The finding that MST cells are tuned for optic flow patterns has led to the suggestion that the area plays an important role in the perception of self-motion. This hypothesis has received further support from studies showing that some MST cells also respond selectively to vestibular cues. Furthermore, the area is part of a network that controls the planning and execution of smooth pursuit eye movements and its activity is modulated by cognitive factors, such as attention and working memory. This review of more than 90 studies focuses on providing clarity of the heterogeneous findings on MST in the macaque cortex and its putative homolog in the human cortex. From this analysis of the unique anatomical and functional position in the hierarchy of areas and processing steps in primate visual cortex, MST emerges as a gateway between perception, cognition, and action planning. Given this pivotal role, this area represents an ideal model system for the transition from sensation to cognition.

In vivo magnetic resonance spectroscopy in the brain of Cdkl5 null mice reveals a metabolic profile indicative of mitochondrial dysfunctions.

Mutations in the X-linked CDKL5 gene cause CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition mainly characterized by infantile epileptic encephalopathy, intellectual disability, and autistic features. The molecular mechanisms underlying the clinical symptoms remain largely unknown and the identification of reliable biomarkers in animal models will certainly contribute to increase our comprehension of CDD as well as to assess the efficacy of therapeutic strategies. Here, we used different Magnetic Resonance (MR) methods to disclose structural, functional, or metabolic signatures of Cdkl5 deficiency in the brain of adult mice. We found that loss of Cdkl5 does not cause cerebral atrophy but affects distinct brain areas, particularly the hippocampus. By in vivo proton-MR spectroscopy (MRS), we revealed in the Cdkl5 null brain a metabolic dysregulation indicative of mitochondrial dysfunctions. Accordingly, we unveiled a significant reduction in ATP levels and a decrease in the expression of complex IV of mitochondrial electron transport chain. Conversely, the number of mitochondria appeared preserved. Importantly, we reported a significant defect in the activation of one of the major regulators of cellular energy balance, the adenosine monophosphate-activated protein kinase (AMPK), that might contribute to the observed metabolic impairment and become an interesting therapeutic target for future preclinical trials. In conclusion, MRS revealed in the Cdkl5 null brain the presence of a metabolic dysregulation suggestive of a mitochondrial dysfunction that permitted to foster our comprehension of Cdkl5 deficiency and brought our interest towards targeting mitochondria as therapeutic strategy for CDD.