a-free-breathing-fmri-method-to-study-human-olfactory-function

A Free-breathing fMRI Method to Study Human Olfactory Function

The study of human olfaction is a highly complex and valuable field with applications ranging from biomedical research to clinical evaluation. Currently, ...

Pennsylvania State University College of Medicine

Olfactory deficits are prevalent in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). These symptoms precede clinical onset of cognitive and memory deficits and coincide with AD pathology preferentially in the central olfactory structures, suggesting a potential biomarker for AD early detection and progression.

Olfactory cortex degeneration in Alzheimer's disease and mild cognitive impairment.

The motor symptoms and signs of early-onset idiopathic Parkinson's disease (PD) in Hoehn and Yahr (H&Y) stage-1 are generally unilateral. We hypothesized that there would be detectable differences in the quantitative MRI parameters in these PD patients between the hemispheres contralateral to the clinically symptomatic and non-symptomatic body side.

MRI evaluation of asymmetry of nigrostriatal damage in the early stage of early-onset Parkinson's disease.

Major depressive disorder (MDD) is associated with dysfunctional corticolimbic networks, making functional connectivity studies integral for understanding the mechanisms underlying MDD pathophysiology and treatment. Resting-state functional connectivity (RSFC) studies analyze patterns of temporally coherent intrinsic brain activity in "resting-state networks" (RSNs). The default-mode network (DMN) has been of particular interest to depression research; however, a single RSN is unlikely to capture MDD pathophysiology in its entirety, and the DMN itself can be characterized by multiple RSNs. This, coupled with conflicting previous results, underscores the need for further research. Here, we measured RSFC in MDD by targeting RSNs overlapping with corticolimbic regions and further determined whether altered patterns of RSFC were restored with electroconvulsive therapy (ECT). MDD patients exhibited hyperconnectivity between ventral striatum (VS) and the ventral default-mode network (vDMN), while simultaneously demonstrating hypoconnectivity with the anterior DMN (aDMN). ECT influenced this pattern: VS-vDMN hyperconnectivity was significantly reduced while VS-aDMN hypoconnectivity only modestly improved. RSFC between the salience RSN and dorsomedial prefrontal cortex was also reduced in MDD, but was not affected by ECT. Taken together, our results support a model of ventral/dorsal imbalance in MDD and further suggest that the VS is a key structure contributing to this desynchronization.

Desynchronization and Plasticity of Striato-frontal Connectivity in Major Depressive Disorder.

Ketamine elicits an acute antidepressant effect in patients with major depressive disorder (MDD). Here, we used diffusion imaging to explore whether regional differences in white matter microstructure prior to treatment may predict clinical response 24h following ketamine infusion in 10 MDD patients.

Structural connectivity and response to ketamine therapy in major depression: A preliminary study.

Mutations within the HFE protein gene sequence have been associated with increased risk of developing a number of neurodegenerative disorders. To this effect, an animal model has been created which incorporates the mouse homologue to the human H63D-HFE mutation: the H67D-HFE knock-in mouse. These mice exhibit alterations in iron management proteins, have increased neuronal oxidative stress, and a disruption in cholesterol regulation. However, it remains undetermined how these differences translate to human H63D carriers in regards to white matter (WM) integrity. To this endeavor, MRI transverse relaxation rate (R2) parametrics were employed to test the hypothesis that WM alterations are present in H63D human carriers and are recapitulated in the H67D mice. H63D carriers exhibit widespread reductions in brain R2 compared to non-carriers within white matter association fibers in the brain. Similar R2 decreases within white matter tracts were observed in the H67D mouse brain. Additionally, an exacerbation of age-related R2 decrease is found in the H67D animal model in white matter regions of interest. The decrease in R2 within white matter tracts of both species is speculated to be multifaceted. The R2 changes are hypothesized to be due to alterations in axonal biochemical tissue composition. The R2 changes observed in both the human-H63D and mouse-H67D data suggest that modified white matter myelination is occurring in subjects with HFE mutations, potentially increasing vulnerability to neurodegenerative disorders.

Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice.

The formation of an odor percept in humans is strongly associated with visual information. However, much less is known about the roles of learning and memory in shaping the multisensory nature of odor representations in the brain.

Rapidly acquired multisensory association in the olfactory cortex.

Patients with major depression show reductions in striatal and paleostriatal volumes. The functional integrity and connectivity of these regions are also shown to change with antidepressant response. Electroconvulsive therapy (ECT) is a robust and rapidly acting treatment for severe depression. However, whether morphological changes in the dorsal and ventral striatum/pallidum relate to or predict therapeutic response to ECT is unknown. Using structural MRI, we assessed cross-sectional effects of diagnosis and longitudinal effects of ECT for volume and surface-based shape metrics of the caudate, putamen, pallidum, and nucleus accumbens in 53 depressed patients (mean age: 44.1 years, 13.8 SD; 52% female) and 33 healthy controls (mean age: 39.3 years, 12.4 SD; 57% female). Patients were assessed before ECT, after their second ECT, and after completing an ECT treatment index. Controls were evaluated at two time points. Support vector machines determined whether morphometric measures at baseline predicted ECT-related clinical response. Patients showed smaller baseline accumbens and pallidal volumes than controls (P<0.05). Increases in left putamen volume (P<0.03) occurred with ECT. Global increases in accumbens volume and local changes in pallidum and caudate volume occurred in patients defined as treatment responders. Morphometric changes were absent across time in controls. Baseline volume and shape metrics predicted overall response to ECT with up to 89% accuracy. Results support that ECT elicits structural plasticity in the dorsal and ventral striatum/pallidum. The morphometry of these structures, forming key components of limbic-cortical-striatal-pallidal-thalamic circuitry involved in mood and emotional regulation, may determine patients likely to benefit from treatment.

Effect of Electroconvulsive Therapy on Striatal Morphometry in Major Depressive Disorder.

Though electroconvulsive therapy (ECT) is an established treatment for severe depression, the neurobiological factors accounting for the clinical effects of ECT are largely unknown. Myo-inositol, a neurometabolite linked with glial activity, is reported as reduced in fronto-limbic regions in patients with depression. Whether changes in myo-inositol relate to the antidepressant effects of ECT is unknown. Using magnetic resonance spectroscopy ((1)H-MRS), we measured dorsomedial anterior cingulate cortex (dmACC) and left and right hippocampal myo-inositol in 50 ECT patients (mean age: 43.78, 14 SD) and 33 controls (mean age: 39.33, 12 SD) to determine cross sectional effects of diagnosis and longitudinal effects of ECT. Patients were scanned prior to treatment, after the second ECT and at completion of the ECT index series. Controls were scanned twice at intervals corresponding to patients' baseline and end of treatment scans. Myo-inositol increased over the course of ECT in the dmACC (p = 0.042). A significant hemisphere by clinical response effect was observed for the hippocampus (p = 0.003) where decreased myo-inositol related to symptom improvement in the left hippocampus. Cross-sectional differences between patients and controls at baseline were not detected. Changes in myo-inositol observed in the dmACC in association with ECT and in the hippocampus in association with ECT-related clinical response suggest the mechanisms of ECT could include gliogenesis or a reversal of gliosis that differentially affect dorsal and ventral limbic regions. Change in dmACC myo-inositol diverged from control values with ECT suggesting compensation, while hippocampal change suggested normalization.

Variations in myo-inositol in fronto-limbic regions and clinical response to electroconvulsive therapy in major depression.

Electroconvulsive therapy (ECT) is a highly effective brain stimulation treatment for severe depression. Identifying neurochemical changes linked with ECT may point to biomarkers and predictors of successful treatment response.

Neurochemical correlates of rapid treatment response to electroconvulsive therapy in patients with major depression.

Age-related olfactory decline, or presbyosmia, is a prevalent condition with potentially devastating consequences on both quality of life and safety. Despite clear evidence for this decline, it is unknown whether presbyosmia is sex-dependent and also whether it is due to central or peripheral olfactory system deterioration. Therefore, the goals of this study were to investigate the neurofunctional substrate of olfactory decline and examine its relationship to age and sex in thirty-seven (18 women, 19 men) healthy older participants using olfactory functional MRI (fMRI). The olfactory fMRI paradigm utilized unique odor+visual and visual-only conditions to contrast peripheral-to-central and central-to-central olfactory processing, respectively. Age was negatively correlated with fMRI activation in olfactory-related regions. Significant aging effects were identifiable in male participants in all target regions. Female participants, however, showed a different pattern of functional decline. Extended unified structural equation modeling (euSEM) analysis revealed that the effective functional connectivity profile was drastically different between male and female participants, with females manifesting a top-down mechanism to offset age-related olfactory activation decline. Our results support the hypotheses that the central olfactory system is involved in age-related olfactory decline, and that resilience to age-related olfactory decline in women may be due to their profuse olfactory network effective connectivity.

Different patterns of age-related central olfactory decline in men and women as quantified by olfactory fMRI.

The risk of cognitive impairment is a concern for patients with major depressive disorder receiving electroconvulsive therapy (ECT). Here, we evaluate the acute, short-term and long-term effects of ECT on tests of processing speed, executive function, memory, and attention.

Short- and Long-term Cognitive Outcomes in Patients With Major Depression Treated With Electroconvulsive Therapy.

Olfactory deficits are present in early Alzheimer's disease (AD) and mild cognitively impaired (MCI) patients. However, whether these deficits are due to dysfunction of the central or peripheral olfactory nervous system remains uncertain. This question is fundamentally important for developing imaging biomarkers for AD using olfactory testing.

Article	Year
Olfactory cortex degeneration in Alzheimer's disease and mild cognitive impairment. Journal of Alzheimer's disease : JAD\| PubMed ID: 25633674	2015
MRI evaluation of asymmetry of nigrostriatal damage in the early stage of early-onset Parkinson's disease. Parkinsonism & related disorders\| PubMed ID: 25825242	2015
Desynchronization and Plasticity of Striato-frontal Connectivity in Major Depressive Disorder. Cerebral cortex (New York, N.Y. : 1991)\| PubMed ID: 26400916	2015
Structural connectivity and response to ketamine therapy in major depression: A preliminary study. Journal of affective disorders\| PubMed ID: 26630613	2016
Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice. Brain imaging and behavior\| PubMed ID: 26660104	2016
Rapidly acquired multisensory association in the olfactory cortex. Brain and behavior\| PubMed ID: 26664785	2015
Effect of Electroconvulsive Therapy on Striatal Morphometry in Major Depressive Disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\| PubMed ID: 27067127	2016
Variations in myo-inositol in fronto-limbic regions and clinical response to electroconvulsive therapy in major depression. Journal of psychiatric research\| PubMed ID: 27285661	2016
Neurochemical correlates of rapid treatment response to electroconvulsive therapy in patients with major depression. Journal of psychiatry & neuroscience : JPN\| PubMed ID: 27327561	2017
Different patterns of age-related central olfactory decline in men and women as quantified by olfactory fMRI. Oncotarget\| PubMed ID: 28454106	2017
Short- and Long-term Cognitive Outcomes in Patients With Major Depression Treated With Electroconvulsive Therapy. The journal of ECT\| PubMed ID: 28617690	2017
Central Olfactory Dysfunction in Alzheimer's Disease and Mild Cognitive Impairment: A Functional MRI Study. Journal of Alzheimer's disease : JAD\| PubMed ID: 28671131	2017

Megha Vasavada

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