Heterozygous GBA D409V and ATP13a2 mutations do not exacerbate pathological α-synuclein spread in the prodromal preformed fibrils model in young mice.

Autophagic dysregulation and lysosomal impairment have been implicated in the pathogenesis of Parkinson's disease, partly due to the identification of mutations in multiple genes involved in these pathways such as GBA, SNCA, ATP13a2 (also known as PARK9), TMEM175 and LRRK2. Mutations resulting in lysosomal dysfunction are proposed to contribute to Parkinson's disease by increasing α-synuclein levels, that in turn may promote aggregation of this protein. Here, we used two different genetic models-one heterozygous for a mutated form of the GBA protein (D409V), and the other heterozygous for an ATP13a2 loss-of-function mutation, to test whether these mutations exacerbate the spread of α-synuclein pathology following injection of α-synuclein preformed fibrils in the olfactory bulb of 12-week-old mice. Contrary to our hypothesis, we found that mice harboring GBA D409V+/- and ATP13a2+/- mutations did not have exacerbated behavioral impairments or histopathology (α-synuclein, LAMP2, and Iba1) when compared to their wildtype littermates. This indicates that in the young mouse brain, neither the GBA D409V mutation or ATP13a2 loss-of-function mutation accelerate the spread of α-synuclein pathology. As a consequence, we postulate that these mutations increase Parkinson's disease risk only by acting in one of the initial, upstream events in the Parkinson's disease pathogenic process. Further, the mutations, and the molecular pathways they impact, appear to play a less important role once the pathogenic process has been triggered and therefore do not specifically influence α-synuclein pathology spread.

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats.

The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemogenetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.

Limbic cortico-striato-thalamo-cortical functional connectivity in drug-naïve patients of obsessive-compulsive disorder.

BACKGROUND: The pathophysiology of obsessive-compulsive disorder (OCD) remains unclear despite extensive neuroimaging work on the disorder. Exposure to medication and comorbid mental disorders can confound the results of OCD studies. The goal of this study was to explore differences in brain functional connectivity (FC) within the cortico-striato-thalamo-cortical (CSTC) loop of drug-naïve and drug-free OCD patients and healthy controls (HCs). METHODS: A total of 29 drug-naïve OCD patients, 22 drug-free OCD patients, and 25 HCs matched on age, gender and education level underwent functional magnetic resonance imaging scanning at resting state. Seed-based connectivity analyses were conducted among the three groups. The Yale Brown Obsessive Compulsive Scale and clinical inventories were used to assess the clinical symptoms. RESULTS: Compared with HCs, the drug-naïve OCD patients had reduced FC within the limbic CSTC loop. In the drug-naïve OCD participants, we also found hyperconnectivity between the supplementary motor area and ventral and dorsal putamen (p < 0.05, corrected for multiple comparisons). CONCLUSIONS: Exposure to antidepressants such as selective serotonin reuptake inhibitors may affect the function of some brain regions. Future longitudinal studies could help to reveal the pharmacotherapeutic mechanisms in these loops.

Normal Olfactory Functional Connectivity Despite Lifelong Absence of Olfactory Experiences.

Congenital blindness is associated with atypical morphology and functional connectivity within and from visual cortical regions; changes that are hypothesized to originate from a lifelong absence of visual input and could be regarded as a general (re) organization principle of sensory cortices. Challenging this is the fact that individuals with congenital anosmia (lifelong olfactory sensory loss) display little to no morphological changes in the primary olfactory cortex. To determine whether olfactory input from birth is essential to establish and maintain normal functional connectivity in olfactory processing regions, akin to the visual system, we assessed differences in functional connectivity within the olfactory cortex between individuals with congenital anosmia (n = 33) and matched controls (n = 33). Specifically, we assessed differences in connectivity between core olfactory processing regions as well as differences in regional homogeneity and homotopic connectivity within the primary olfactory cortex. In contrast to congenital blindness, none of the analyses indicated atypical connectivity in individuals with congenital anosmia. In fact, post-hoc Bayesian analysis provided support for an absence of group differences. These results suggest that a lifelong absence of olfactory experience has a limited impact on the functional connectivity in the olfactory cortex, a finding that indicates a clear difference between sensory modalities in how sensory cortical regions develop.

Association between olfactory function and inhibition of emotional competing distractors in major depressive disorder.

We aimed to investigate the changes of olfaction of major depressive disorder (MDD) before and after medical treatment, and to preliminarily scrutinize the association between the olfactory function and the severity of depressive symptoms, response inhibition, and emotional responding. Forty-eight medicine-naïve MDD patients plus 33 healthy controls (HC) matched on gender, ages, and level of education, were recruited in the test group. The Chinese Smell Identification Test (CSIT), Self-reported Olfactory Scale (SROS), 17-item Hamilton Depression Rating Scale (HAMD-17), Hamilton Anxiety Rating Scale (HAMA), and mean reaction time/accuracy rate (ΔMRT) of emotional Stroop test were measured. The patients were assessed before the treatment (baseline) and 3 months after the treatment (follow-up). The data at the baseline level were measured then associated using multiple linear regression stepwise analysis. The MDD patients had lower scores of the CSIT and SROS and longer ΔMRT at baseline level compared to HC while the ΔMRT of MDD patients remained longer after 3-month treatment (p's < 0.05). At the baseline level, the regression equation including age and ΔMRT of negative word-color congruent (NEG-C), was finally observed as follows: y(CSIT) = 10.676-0.063 × 1-0.002 × 2, [x1 = the age(y), x2 = the NEG-C (ms)]. The olfactory function of MDD appears to be correlated negatively with the age and the ΔMRT of negative stimuli before treatment. After the remission of MDD, the olfactory dysfunction was improved, which might be regarded as a responding phenotype of brain function of MDD rather than the emotional responding.

Disruptions of the olfactory and default mode networks in Alzheimer's disease.

INTRODUCTION: Olfactory deficits are prevalent in early Alzheimer's disease (AD) and are predictive of progressive memory loss and dementia. However, direct neural evidence to relate AD neurodegeneration to deficits in olfaction and memory is limited. METHODS: We combined the University of Pennsylvania Smell Identification Test (UPSIT) with olfactory functional magnetic resonance imaging (fMRI) to investigate links between neurodegeneration, the olfactory network (ON) and the default mode network (DMN) in AD. RESULTS: Behaviorally, olfactory and memory scores showed a strong positive correlation in the study cohorts. During olfactory fMRI, the ON showed reduced task-related activation and the DMN showed reduced task-related suppression in mild cognitive impairment (MCI) and AD subjects compared to age-matched cognitively normal subjects. CONCLUSIONS: The results provide in vivo evidence for selective vulnerability of ON and DMN in AD and significantly improves the viable clinical applications of olfactory testing. A network-based approach, focusing on network integrity rather than focal pathology, seems beneficial to olfactory prediction of dementia in AD.

Advances in Understanding Parosmia: An fMRI Study.

INTRODUCTION: A number of patients with a diminished sense of smell also can suffer from parosmia. These patients with such a qualitative smell disorder are often more severely affected than patients exhibiting only a quantitative smell disorder. Qualitative smell disorders have heretofore been poorly investigated. The focus of the present study was, using functional MRI, to compare the central processing of olfactory stimulation in patients with qualitative smell disorders. MATERIAL AND METHODS: A total of 23 patients were investigated, 12 hyposmic patients without parosmia (HYP group) and 11 hyposmic patients with parosmia (PAR group). Both groups were matched with regard to sex and age. The olfactory smells used were peach and coffee odors. RESULTS: The two groups exhibited different patterns of activation. In HYP patients a stronger activation was observed in the medial orbitofrontal cortex, anterior cingulate cortex, and parahippocampal gyrus, whereas in the PAR group stronger activation in the thalamus and putamen was seen. DISCUSSION: These results are consistent with the hypothesis that there are specific patterns in the central processing of olfactory stimuli which differ in hyposmic patients with and without parosmia.

Causal Interactions in Human Amygdala Cortical Networks across the Lifespan.

There is growing evidence that the amygdala serves as the base for dealing with complex human social communication and emotion. Although amygdalar networks plays a central role in these functions, causality connectivity during the human lifespan between amygdalar subregions and their corresponding perception network (PerN), affiliation network (AffN) and aversion network (AveN) remain largely unclear. Granger causal analysis (GCA), an approach to assess directed functional interactions from time series data, was utilized to investigated effective connectivity between amygdalar subregions and their related networks as a function of age to reveal the maturation and degradation of neural circuits during development and ageing in the present study. For each human resting functional magnetic resonance imaging (fMRI) dataset, the amygdala was divided into three subareas, namely ventrolateral amygdala (VLA), medial amygdala (MedA) and dorsal amygdala (DorA), by using resting-state functional connectivity, from which the corresponding networks (PerN, AffN and AveN) were extracted. Subsequently, the GC interaction of the three amygdalar subregions and their associated networks during life were explored with a generalised linear model (GLM). We found that three causality flows significantly varied with age: the GC of VLA → PerN showed an inverted U-shaped trend with ageing; the GC of MedA→ AffN had a U-shaped trend with ageing; and the GC of DorA→ AveN decreased with ageing. Moreover, during ageing, the above GCs were significantly correlated with Social Responsiveness Scale (SRS) and State-Trait Anxiety Inventory (STAI) scores. In short, PerN, AffN and AveN associated with the amygdalar subregions separately presented different causality connectivity changes with ageing. These findings provide a strong constituent framework for normal and neurological diseases associated with social disorders to analyse the neural basis of social behaviour during life.

Electrophysiological Characteristics of the Migraine Brain: Current Knowledge and Perspectives.

BACKGROUND: Despite pain being its most prominent feature, migraine is primarily a disorder of sensory processing. Electrophysiology-based research in the field has consistently developed over the last fifty years. OBJECTIVE: To summarize the current knowledge on the electrophysiological characteristics of the migraine brain, and discuss perspectives. METHODS: We critically reviewed the literature on the topic to present and discuss articles selected on the basis of their significance and/or novelty. RESULTS: Physiologic fluctuations within time, between-subject differences, and methodological issues account as major limitations of electrophysiological research in migraine. Nonetheless, several abnormalities revealed through different approaches have been described in the literature. Altogether, these results are compatible with an abnormal state of sensory processing. PERSPECTIVES: The greatest contribution of electrophysiological testing in the future will most probably be the characterization of sub-groups of migraine patients sharing specific electrophysiological traits. This should serve as strategy towards personalized migraine treatment. Incorporation of novel methods of analysis would be worthwhile.

Impaired Odor Perception in Autism Spectrum Disorder Is Associated with Decreased Activity in Olfactory Cortex.

Autism Spectrum Disorders (ASDs) are characterized by atypical sensory functioning in the visual, tactile, and auditory systems. Although less explored, olfactory changes have been reported in ASD patients. To explore these changes on a neural level, 18 adults with ASD and 18 healthy neurotypical controls were examined in a 2-phase study. Participants were first tested for odor threshold and odor identification. Then, (i) structural magnetic resonance (MR) images of the olfactory bulb were acquired, and (ii) a functional MR imaging olfaction study was conducted. ASD patients exhibited decreased function for odor thresholds and odor identification; this was accompanied by a relatively decreased activation in the piriform cortex. In conclusion, these findings suggest, that the known alterations in olfaction in ASD are rooted in the primary olfactory cortex.

Olfactory functioning in adults with Tourette syndrome.

Tourette syndrome is a chronic tic disorder characterized by motor and vocal tics. Comorbidities such as attention deficit hyperactivity disorder and obsessive compulsive disorder can be found. The overlap between neuroanatomical regions and neurotransmitter systems in the olfactory system and the pathophysiology of Tourette syndrome let us hypothesize altered olfactory performance in Tourette syndrome. The main objective of this study was to systematically assess olfactory functioning in subjects with Tourette syndrome and to compare it to healthy controls. We assessed 28 adults with Tourette syndrome (age 33.1±9.4 years, disease duration 23.7±9.7 years) and 28 healthy controls (age 32.9±9.0 years) matched in regard to age, sex, education and smoking habits. The "Sniffin Sticks" test battery was applied to assess odor threshold, discrimination, and identification. Additionally, the combined score of the odor threshold test, the odor discrimination test and the odor identification test of the "Sniffin Sticks" test battery was calculated. Although it was not the primary aim of this study, we assessed whether tics and comorbidity could contribute to olfactory alterations in adults with Tourette syndrome. Therefore, clinical scores were used to assess severity of tics and co-morbidity such as attention deficit hyperactivity disorder, obsessive compulsive disorder, anxiety and depression in subjects with Tourette syndrome. Pathology of the nasal cavities was excluded with rhinoendoscopy. Independent sample t-tests were applied to compare performance in olfactory tests. In the case of statistically significant differences (critical p-value: 0.05), multiple linear regression analysis was carried out to explore whether tic severity, social impairment, co-morbidity or medical treatment had an impact on the differences found. Descriptive values are reported as mean ± standard deviation. Tourette syndrome subjects showed lower combined scores (Tourette syndrome subjects 31.9 ± 5.1 versus healthy controls 35.0 ± 3.1; p = 0.007), odor identification scores (Tourette syndrome subjects 12.4 ± 2.0 versus healthy controls 13.7 ± 1.4; p = 0.008) and odor discrimination scores (Tourette syndrome subjects 12.1 ± 2.1 versus healthy controls 13.2 ± 1.6; p = 0.041) in comparison to healthy subjects, while there was no difference in odor threshold (Tourette syndrome subjects 7.3 ± 2.7 versus healthy controls 8.1 ± 2.2; p = 0.22). Seven out of 28 Tourette syndrome subjects (25%) scored in the range of the age- and sex-dependent combined score for hyposmia, while two of 28 healthy controls (7%) had a similar low combined score. None of the participants were found to have functional anosmia. Multiple linear regression analyses suggest that social impairment may a predictor for low combined score and odor identification score in Tourette syndrome subjects (p = 0.003). Compared to healthy controls, altered olfaction in adults with Tourette syndrome was found in this study. Normal odor threshold level but lower scores at tasks involving supra-threshold odor concentrations point towards a central-nervous alteration in the processing of olfactory information in Tourette syndrome.

A Novel Focal Seizure Pattern Generated in Superficial Layers of the Olfactory Cortex.

Seizure patterns identified in focal epilepsies caused by diverse etiologies are likely due to different pathogenic mechanisms. We describe here a novel, region-specific focal seizure pattern that mimics seizure activity observed in a subpopulation of patients submitted to presurgical monitoring with intracerebral electrodes. Distinctive seizure-like events (SLEs) are induced in the olfactory regions by acute treatment of both tangential brain slices and the isolated guinea pig brain with the potassium channel blocker 4-aminopyridine. Analysis of field potentials, intracellular activities, and extracellular potassium changes demonstrates that SLEs in the piriform cortex initiate in the superficial layer 1 lacking principal neurons with an activity-dependent increase of extracellular potassium. SLE progression (but not onset) does not require the participation of synaptic transmission and is mediated by diffusion of potassium to deep cortical layers. The novel seizure pattern here described is not observed in other cortical regions; it is proposed to rely on the peculiar organization of the superficial piriform cortex layers, which are characterized by unmyelinated axons and perisynaptic astroglial envelopes. This study reveals a sequence of ictogenic events in the olfactory cortex that were never described before in other cortical structures and supports the notion that altered potassium homeostasis and unmyelinated fibers may represent a potential vehicle for focal ictogenesis.SIGNIFICANCE STATEMENT We describe a novel seizure pattern peculiar of the olfactory cortex that resembles focal seizures with low-voltage fast activity at onset observed in humans. The findings suggest that network mechanisms responsible for seizure onset can be region specific.

Morphological analysis of regenerated bulbar fibers in relation to neonatal olfaction.

It was revealed that regeneration of the lateral olfactory tract (LOT) occurred in developing rats and the regenerated olfactory system was functional 4 weeks after transection. The aim of this study was to determine the earliest onset of functional recovery in LOT-injured rats and to quantify regenerated nerve components with functional correlation. Neonatal rats on postnatal day (P) 2 were subjected to unilateral transection of the left LOT and underwent unilateral removal of the right olfactory bulb on P11. Functional recovery of the tract injury was assessed by the suckling capability, which can be achieved by olfaction. Suckling capability was observed on P12 in most neonatally LOT-transected pups. Rat pups were subjected to unilateral transection of the left LOT on P2, and received injections of biotinylated dextran amine (BDA) into the bilateral olfactory bulb on P5 to quantify normal and regenerated nerve components in the olfactory cortices at the level of the olfactory tubercle. BDA(+) areas and density indices of the olfactory cortices in the neonatally LOT-transected P12 pups were 11.05×105µm2 and 0.35 on the normal right side and 4.34×105µm2 and 0.21 on the transected left side. We concluded that functional recovery of the LOT-transected neonatal rats occurred as early as 10days after tract transection and that areas and densities of regenerated nerve components essential for functional recovery were approximately 40% and 60% of the age-matched normal values in the olfactory cortices at the level of the olfactory tubercle.

Back on the scent: the olfactory system in CNS demyelinating diseases.

Olfactory dysfunction is recognised across an ever broadening spectrum of neuropsychiatric conditions including central nervous system (CNS) demyelinating diseases such as multiple sclerosis (MS) and neuromyelitis optica (NMO). In this review, we unravel the striking evidence highlighting how olfactory loss is a common clinical feature in MS and NMO. We provide an overview of the supportive psychophysical, electrophysiological, radiological and pathological data that point to the anatomical substrate of olfactory deficits in these diseases. The pattern of underlying pathology affecting the olfactory system is shown to be complex, involving multiple structures that are affected in different ways throughout the course of the disease. This review is the first to synthesise the expanding body of literature on the topic, provides novel insight into the way in which the olfactory system is affected in CNS demyelinating diseases, and raises intriguing questions about the role of this system in the pathogenesis of these diseases.

[OLFACTORY EEG PATTERNS OF MENTAL AND BEHAVIORAL DISORDERS DUE TO PSYCHOACTIVE SUBSTANCE USE].

The 74 persons, including the 39 persons with mental and behavioral disorders due to psychoactive substance use (PAS) and the 35 persons with subclinical forms of substance use, are examined. The olfactory EEG patterns, differing in narcological patients depending on the range of PAS used, are revealed. EEG markers of olfactory response to isopropanol, thymol and androstenone in combination with emotional evaluation, having hemispheric features, can be diagnostic and differential predictive factors for assessment of predisposition to mental and behavioral disorders due to PAS use.

Facial Characteristics and Olfactory Dysfunction: Two Endophenotypes Related to Nonsyndromic Cleft Lip and/or Palate.

Evidence exists for the presence of a specific facial phenotype in nonaffected first-degree relatives of persons with CL/P. An increased risk for olfactory dysfunction has also been reported in CL/P-relatives. These phenotypic features can probably be explained via the presence of CL/P-related susceptibility genes. We aimed at confirming the occurrence of these endophenotypic traits in first-degree CL/P-relatives, and we investigated the link between the facial phenotype and the smell capacity in this group. We studied the facial morphology of 88 nonaffected first-degree relatives of patients with CL/P and 33 control subjects without family history of facial clefting by 3D surface imaging and a spatially dense analysis of the images. Smell testing was performed in 30 relatives and compared with 23 control subjects. Nonaffected relatives showed midface retrusion, hypertelorism, and olfactory dysfunction, compared to controls. In addition, we show for the first time that olfactory dysfunction in relatives is correlated to a smaller upper nasal region. This might be explained by a smaller central olfactory system. The different facial morphology in the relatives with olfactory impairment as compared to the total group may be an illustration of the contribution of different genetic backgrounds to the occurrence of CL/P via different biological pathways.

Migraine is associated with altered processing of sensory stimuli.

Migraine is associated with derangements in perception of multiple sensory modalities including vision, hearing, smell, and somatosensation. Compared to people without migraine, migraineurs have lower discomfort thresholds in response to special sensory stimuli as well as to mechanical and thermal noxious stimuli. Likewise, the environmental triggers of migraine attacks, such as odors and flashing lights, highlight basal abnormalities in sensory processing and integration. These alterations in sensory processing and perception in migraineurs have been investigated via physiological studies and functional brain imaging studies. Investigations have demonstrated that migraineurs during and between migraine attacks have atypical stimulus-induced activations of brainstem, subcortical, and cortical regions that participate in sensory processing. A lack of normal habituation to repetitive stimuli during the interictal state and a tendency towards development of sensitization likely contribute to migraine-related alterations in sensory processing.

Gray matter volume reduction of olfactory cortices in patients with idiopathic olfactory loss.

Idiopathic olfactory loss (IOL) is a common olfactory disorder. Little is known about the pathophysiology of this disease. Previous studies demonstrated decreased olfactory bulb (OB) volume in IOL patients when compared with controls. The aim of our study was to investigate structural brain alterations in areas beyond the OB. We acquired T1-weighted magnetic resonance images from 16 patients with IOL and from 16 age- and sex-matched controls on a 3T scanner. Voxel-based morphometry (VBM) was performed using VBM8 toolbox and SPM8 in a Matlab environment. Psychophysical testing confirmed that patients had higher scores for Toyota and Takagi olfactometer and lower scores for Sniffin' Sticks olfactory test than controls (t = 46.9, P < 0.001 and t = 21.4, P < 0.001, respectively), consistent with olfactory dysfunction. There was a significant negative correlation between the 2 olfactory tests (r = -0.6, P = 0.01). In a volume of interest analysis including primary and secondary olfactory areas, we found patients with IOL to exhibit gray matter volume loss in the orbitofrontal cortex, anterior cingulate cortex, insular cortex, parahippocampal cortex, and the piriform cortex. The present study indicates that changes in the central brain structures proximal to the OB occur in IOL. Further investigations of this phenomenon may be helpful to elucidate the etiology of IOL.