Ivanka Savic

Olfactory Functions Are Mediated by Parallel and Hierarchical Processing

How the human brain processes the perception, discrimination, and recognition of odors has not been systematically explored. Cerebral activations were therefore studied with PET during five different olfactory tasks: monorhinal smelling of odorless air (AS), single odors (OS), discrimination of odor intensity (OD-i), discrimination of odor quality (OD-q), and odor recognition memory (OM). OS activated amygdala-piriform, orbitofrontal, insular, and cingulate cortices and right thalamus. OD-i and OD-q both engaged left insula and right cerebellum. OD-q also involved other areas, including right caudate and subiculum. OM did not activate the insula, but instead, the piriform cortex. With the exception of caudate and subiculum, it shared the remaining activations with the OD-q, and engaged, in addition, the temporal and parietal cortices. These findings indicate that olfactory functions are organized in a parallel and hierarchical manner.

Smelling of Odorous Sex Hormone-like Compounds Causes Sex-Differentiated Hypothalamic Activations in Humans

The anatomical pathways for processing of odorous stimuli include the olfactory nerve projection to the olfactory bulb, the trigeminal nerve projection to somatosensory and insular cortex, and the projection from the accessory olfactory bulb to the hypothalamus. In the majority of tetrapods, the sex-specific effects of pheromones on reproductive behavior is mediated via the hypothalamic projection. However, the existence of this projection in humans has been regarded as improbable because humans lack a discernable accessory olfactory bulb. Here, we show that women smelling an androgen-like compound activate the hypothalamus, with the center of gravity in the preoptic and ventromedial nuclei. Men, in contrast, activate the hypothalamus (center of gravity in paraventricular and dorsomedial nuclei) when smelling an estrogen-like substance. This sex-dissociated hypothalamic activation suggests a potential physiological substrate for a sex-differentiated behavioral response in humans.

PET and MRI show differences in cerebral asymmetry and functional connectivity between homo- and heterosexual subjects

Cerebral responses to putative pheromones and objects of sexual attraction were recently found to differ between homo- and heterosexual subjects. Although this observation may merely mirror perceptional differences, it raises the intriguing question as to whether certain sexually dimorphic features in the brain may differ between individuals of the same sex but different sexual orientation. We addressed this issue by studying hemispheric asymmetry and functional connectivity, two parameters that in previous publications have shown specific sex differences. Ninety subjects [25 heterosexual men (HeM) and women (HeW), and 20 homosexual men (HoM) and women (HoW)] were investigated with magnetic resonance volumetry of cerebral and cerebellar hemispheres. Fifty of them also participated in PET measurements of cerebral blood flow, used for analyses of functional connections from the right and left amygdalae. HeM and HoW showed a rightward cerebral asymmetry, whereas volumes of the cerebral hemispheres were symmetrical in HoM and HeW. No cerebellar asymmetries were found. Homosexual subjects also showed sex-atypical amygdala connections. In HoM, as in HeW, the connections were more widespread from the left amygdala; in HoW and HeM, on the other hand, from the right amygdala. Furthermore, in HoM and HeW the connections were primarily displayed with the contralateral amygdala and the anterior cingulate, in HeM and HoW with the caudate, putamen, and the prefrontal cortex. The present study shows sex-atypical cerebral asymmetry and functional connections in homosexual subjects. The results cannot be primarily ascribed to learned effects, and they suggest a linkage to neurobiological entities.

MR spectroscopy shows reduced frontal lobe concentrations of N-acetyl aspartate in patients with juvenile myoclonic epilepsy

Summary: Purpose: Neuropsychological studies suggest frontal lobe dysfunctions in patients with juvenile myoclonic epilepsy (JME). In this study we investigated whether an underlying mechanism could be a regional neuronal damage not visible with structural magnetic resonance (MR), but detectable with magnetic resonance spectroscopy (MRS).

Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy

Objective: To test the hypothesis that in mesial temporal lobe epilepsy (MTLE) there is involvement outside of mesial structures and that this involvement affects serotonin systems, thus suggesting a mechanism for affective symptoms in this population. Methods: Serotonin 5-HT1A receptor binding was studied with PET and [Carbonyl-11C]WAY-100 635 in 14 patients (6 with left-, 8 with right-sided mesial temporal lobe focus) and 14 controls. The 5-HT1A receptor binding potential was calculated for hippocampus, amygdala, orbitofrontal, insular, lateral temporal, and anterior cingulate cortex, in raphe nuclei, and in two regions presumably uninvolved in the epileptogenic process (parietal, and dorsolateral frontal neocortex). Results: The binding potential was reduced in the epileptogenic hippocampus (p = 0.0001) and amygdala (p = 0.0001) in all patients, including the six with normal [18F]FDG PET and MRI. It was also reduced in the anterior cingulate (p = 0.002), insular (p = 0.015), and lateral temporal cortex (p = 0.029) ipsilaterally to the focus, in contralateral hippocampus (p = 0.025), and in the raphe nuclei (p = 0.016). Conclusion: Patients with severe MTLE show reduced 5-HT1A receptor binding potential in the EEG-focus, and its limbic connections. [11C]WAY-100 635 PET may provide additional information to EEG, [18F]FDG PET, and MRI when evaluating patients with intractable seizures. Reductions in 5-HT1A binding in the insula and cingulate suggest a mechanism by which affective symptoms in MTLE may result.

[11C]Flumazenil Positron Emission Tomography Visualizes Frontal Epileptogenic Regions

Summary: Presently available noninvasive methods correctly localize epileptogenic regions in only ε50% of patients with frontal lobe epilepsy (FLE). Earlier studies have shown that temporal lobe epileptogenic regions may be identified readily by positron emission tomography (PET) measurements of regional benzodiazepine (BZD) receptor binding. We tested the specific applicability of this method in patients with FLE. Six patients with frontal partial seizures and 7 healthy men were investigated with PET and the BZD receptor ligand [11C]flumazenil. All patients had magnetic resonance (MR) brain scans. The independent assessment of seizure–onset region was based on seizure semiology, intra– and extracranial EEG and, in 4 cases, also on [18F]fluorodeoxyglucose (FDG) PET. The epileptic focus/seizure‐generating region was correctly identified by [11C]flumazenil PET in all patients. This region was characterized by a significant reduction in BZD receptor density. The area with reduced BZD receptor density was better delimited than the corresponding hypometabolic region, which was observed in 50% of patients investigated with [18F]FDG–PET. MRI was normal in 5 patients. Visualization of BZD receptors with [11C]flumazenil PET appears to be a promising approach for noninvasive identification of frontal lobe epileptogenic regions.

Imaging of brain activation by odorants in humans

Application of positron emission tomography and magnetic resonance imaging has provided several new insights into various olfactory functions. One is that sniffing and smelling engage separate subsystems in the human olfactory cortex. Another is that perception of odorous compounds (odorants) is mediated by a set of core regions, which are partly different for pure olfactory than for olfactory plus trigeminal odorants. Depending on the task associated with odor perception, the core regions are recruited together with other circuits, in a parallel and hierarchical manner. The sense of smell seems, therefore, to be organized similarly to other sensory modalities, and the specific psychophysical characteristics of olfaction should be attributed to an early involvement of the limbic system rather than to a conceptually different mode of processing.

MRS shows syndrome differentiated metabolite changes in human-generalized epilepsies

OBJECTIVE While it is generally accepted that the thalamo-cortical loop is abnormal in idiopathic generalized epilepsy (IGE), it is uncertain whether this loop is similarly affected among different IGE syndromes. We recently demonstrated reduced frontal lobe levels of N-acetyl aspartate (NAA) in patients with juvenile myoclonic epilepsy (JME). The present follow-up study investigates if similar or other types of changes exist in subjects with pure primarily generalized tonic clonic epilepsy (GTCS). METHOD Twenty patients with GTCS, 26 patients with JME, and 10 matched healthy controls were investigated with quantitative single voxel MR spectroscopy (MRS) measurements of NAA, choline (Cho), creatine (Cr), and myo-inositol (mI) at 1.5 T scanner. The voxels were placed over the right cerebellum, right thalamus, prefrontal, occipital cortex, and over a spherical phantom above the subjects head. RESULTS Patients with JME had reduced frontal lobe NAA (mmol/l) in relation to controls (9.8 +/- 1.1 vs. 10.8 +/- 0.7, P = 0.01), as well as GTCS patients (9.8 +/- 1.1 vs. 10.6 +/- 0.7, P = 0.007), whose values were normal. Patients with GTCS, on the other hand, showed significantly lower thalamic NAA than controls (9.7 +/- 1.0 vs. 10.8 +/- 0.9, P = 0.002), and both groups of patients had reduced thalamic Cho, and mI; [CHO: 2.0 +/- 0.4 (control) vs. 1.61 +/- 0.3 (JME) P = 0.001, and vs. 1.57 +/- 0.3 (GTCS) P = 0.0005; MI: 4.8 +/- 1.5 (control) vs. 3.3 +/- 1.4 (JME) P = 0.003, and vs. 3.2 +/- 1.5 (GTCS), P = 0.002]. No other regional changes were observed. CONCLUSION The present MRS data emphasize the involvement of thalamus in IGE. They also show partly differentiated alterations within the thalamo-cortical loop in JME vs. GTCS. The various clinical expressions of IGE may, thus, be associated with more localized neuroanatomical substrates than generally believed.

PET shows that odors are processed both ipsilaterally and contralaterally to the stimulated nostril.

The olfactory nerve is the only cranial nerve with established ipsilateral primary cerebral anatomical projections. Whether these projections correspond to the functional pathways for monorhinal processing of odor perception is, however, unknown. We therefore studied cerebral blood flow (rCBF) with [15O]butanol-PET in 18 healthy females during monorhinal smelling of single odors (OS) and odorless air (AS). Compared with AS, OS activated right amygdala and piriform cortex (confluent cluster), right orbitofrontal cortex, left insula, right thalamus, and anterior cingulate. A post hoc analysis showed that the first three regions were activated independently of the stimulated side, but that right orbitofrontal rCBF was higher during the right nostril stimulations. Left insula was activated mainly by the right nostril stimuli, and right thalamus by the left nostril stimuli. Odors seem to be processed both ipsi and contralaterally, with a right hemisphere preponderance irrespective of the stimulated nostril.

Brain activation during odor perception in males and females.

Several studies indicate that women outperform men in olfactory identification tasks. The psychophysical data are more divergent when it comes to gender differences at levels of odor processing which are cognitively less demanding. We therefore compared cerebral activation with H215O PET in 12 females and 11 males during birhinal passive smelling of odors and odorless air. The odorous compounds (odorants) were pure olfactory, or mixed olfactory and weakly trigeminal. Using odorless air as the baseline condition, activations were found bilaterally in the amygdala, piriform and insular cortices in both sexes, irrespective of the odor. No gender difference was detected in the pattern of cerebral activation (random effect analysis SPM99, corrected p < 0.05) or in the subjective perception of odors. Males and females seem to use similar cerebral circuits during the passive perception of odors. The reported female superiority in assessing olfactory information including odor identification is probably an effect of a difference at a cognitive, rather than perceptive level of olfactory processing.