Lucien M. Levy

Rapid modulation of GABA in sensorimotor cortex induced by acute deafferentation

Recovery of function after acute injury to the central nervous system may be controlled by the availability of γ‐aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cerebral cortex. Acute lesions as well as manipulation of sensory inputs can lead to rapid reorganization of the cerebral cortex, occurring within minutes to hours. Reduction of cortical inhibitory tone through a decrease in the availability of GABA has been suggested as a possible mechanism; however, the degree and temporal course of the changes in brain GABA are not known. A novel method using two‐dimensional J‐resolved magnetic resonance spectroscopy showed that GABA levels in the human sensorimotor cortex are quickly reduced within minutes of deafferentation. This finding strongly supports the view that the release of latent corticocortical projections from tonic inhibition through decreased GABA availability is a mechanism of rapid cortical plasticity. Reduction of brain GABA can play a pivotal role in regulating the extent of rapid cortical reorganization after lesions or changes in sensory input. Ann Neurol 2002;52:000–000

Functional Mri of Human Olfaction

PURPOSE Our goal was to use functional MRI (fMRI) to measure brain activation in response to olfactory stimuli. METHOD fMRI brain scans were obtained in 17 normal subjects (9 men, 8 women) using-multislice FLASH MRI in response to three olfactory stimuli (pyridine, menthone, amyl acetate) in three coronal brain sections selected from anterior to posterior temporal brain regions. Activation images were derived using correlation analysis, and ratios of areas of brain activated to total brain areas were calculated. RESULTS Activation was present in each section in all subjects. Subjective estimation of vapor intensity followed relative vapor pressure of stimuli presented (pyridine > amyl acetate > menthone) and were similar for both men and women. However, brain activation did not follow subjective responsiveness order but rather pyridine > menthone > amyl acetate, a pattern demonstrated by both men and women. Brain activation in women was consistently lower than in men for all vapors in all brain sections, although regions of activation did not differ. Activation occurred in regions previously recognized as associated with olfactory stimulation, including orbitofrontal and entorhinal cortex; however, extensive regions within frontal cortex including cingulate gyrus were also activated. Brain regions activated to odors considered pleasant or unpleasant did not differ. CONCLUSION The techniques used in this study demonstrated that brain activation to olfactory stimuli could be measured quantitatively such that differences between groups of subjects (in this case men and women) could be compared. Although localization of brain activation was not the major thrust of this study, activation to olfactory stimuli was found not only in brain regions previously associated with processing of olfactory information but also in several other areas of frontal cortex, in cingulate gyrus, and in several components of the limbic system. This is the first study in which activation in human brain parenchyma of normal humans to olfactory stimuli has been quantitated by fMRI.

Odor memory induces brain activation as measured by functional MRI.

PURPOSE Our goal was to use functional MRI (fMRI) to measure brain activation in response to imagination of odors in humans. METHOD fMR brain scans were obtained in 21 normal subjects (9 men, 12 women) using multislice FLASH MRI in response to imagination of odors of banana and peppermint and to the actual smells of the corresponding odors of amyl acetate and menthone, respectively, in three coronal sections selected from anterior to posterior temporal brain regions. Similar studies were obtained in two patients with hyposmia using FLASH MRI and in one patient with hyposmia using echo planar imaging, both before and after theophylline treatment, which returned smell function to or toward normal in each patient. Activation images were derived using correlation analysis, and ratios of areas of brain activated to total brain areas were calculated. RESULTS Activation was present in each section in all normal subjects and in each patient after imagination of each vapor. In normal subjects, brain activation in response to imagination of odors was significantly less than that in response to the actual smell of these odors, and activation following imagination of banana odor was significantly greater in men than in women, as was previously reported for the actual smell of the odor of amyl acetate. However, in relative terms, albeit at an absolute lower brain activation level, the ratio of brain activation by imagination of banana to activation by actual amyl acetate odor was about twice as high in women as in men. Before treatment, in patients with hyposmia, brain activation in response to odor imagination was greater than after presentation of the actual odor itself. After treatment, in patients with hyposmia in whom smell acuity returned to or toward normal, brain activation in response to odor imagination was not significantly different quantitatively from that before treatment; however, brain activation in response to the actual odor was significantly greater than that in response to imagination of the corresponding odor. Brain regions activated by both odor imagination and actual corresponding odor were similar and consistent with regions previously described as responding to odors. CONCLUSION These studies indicate that (a) odors can be imagined and similar brain regions are activated by both imagined and corresponding actual odors; (b) imagination of odors elicits quantitatively less brain activation than do actual smells of corresponding odors in normal subjects; (c) absolute brain activation in men by odor imagination is greater than in women for some odors, but on a relative basis, the ratio for odor imagination to actual smell in women is twice that in men; (d) odor imagination, once the odor has been experienced, is present, recallable, and capable of inducing a relatively constant degree of brain activation even in the absence of the ability to recognize an actual corresponding odor.

Taste memory induces brain activation as revealed by functional MRI.

PURPOSE Our goal was to use functional MRI (fMRI) to measure brain activation in response to imagination of tastes in humans. METHOD fMR brain scans were obtained in 31 subjects (12 men, 19 women) using multislice FLASH MRI and echo planar imaging (EPI) in response to imagination of tastes of salt and sweet in coronal sections selected from anterior to posterior temporal brain regions. Activation images were derived using correlation analysis, and ratios of areas of brain activated to total brain areas were calculated. Total activated pixel counts were used to quantitate regional brain activation. RESULTS Activation was present in each section in all subjects after imagination of each tastant. Activation was similar in response to imagination of either salt or sweet and was quantitatively similar to that previously reported in response to imagination of odors of banana and peppermint. Activation was similar in both men and women as opposed to previous results of odor memory in which activation in men was greater than in women. However, subjective responses of intensity of imagined tastes were significantly greater than those previously obtained for odor memory and were consistently, albeit not significantly, greater in women than in men, similar to results previously reported for odor memory. Brain regions activated in response to taste imagination were consistent with regions previously described as involved with actual taste perception in both humans and animals. Regional brain localization for salt and sweet memories could not be differentiated. CONCLUSION These studies indicate that (a) tastes can be imagined, (b) brain regions activated for taste imagination are consistent with regions previously described for actual taste perception, and (c) similar to odor memory for banana and menthone, regional brain localization for salt or sweet taste memories could not be differentiated.

Increased brain activation in response to odors in patients with hyposmia after theophylline treatment demonstrated by fMRI

PURPOSE Our goal was to demonstrate that medical therapy in patients with smell loss (hyposmia) that restored olfactory function toward or to normal could be verified and quantitated by functional MRI (fMRI) of brain and that visual representation of these changes could be used to identify these patients. METHOD Multislice FLASH MR or echo planar MR brain scans were obtained in four patients with hyposmia in response to three olfactory stimuli both before and after treatment with theophylline. Activation images were derived using correlation analysis, and ratios of brain area activated to total brain area were obtained. RESULTS Prior to treatment, all patients stated that they could not smell; these losses were confirmed by standard psychophysical tests. At this time, fMRI brain activation in response to odors was significantly less than that measured in normal volunteers and similar to activation measured previously in other patients with a similar type of hyposmia. After treatment, subjective smell function improved in three patients and no improvement occurred in one; results were confirmed by psychophysical tests. In each patient in whom smell acuity improved, brain activation in response to each odor increased in each section and mean activation increased significantly for each odor. Activation increased in all regions previously associated with olfactory stimulation and was particularly apparent in orbitofrontal cortex, frontal lobe component of cingulate gyri, temporal lobe gyri, and hippocampus. There also was consistent activation in superior, middle, and inferior frontal lobe gyri. There were no changes in brain activation after treatment in the patient in whom smell did not improve. CONCLUSION These results demonstrate that theophylline is an effective therapeutic agent to correct hyposmia in some patients with smell loss. These changes have been documented by fMRI brain scans using olfactory stimuli. This is the first study in which this type of objective improvement following medical treatment has been demonstrated in patients with hyposmia.

Path Integration Deficits during Linear Locomotion after Human Medial Temporal Lobectomy

Animal navigation studies have implicated structures in and around the hippocampal formation as crucial in performing path integration (a method of determining ones position by monitoring internally generated self-motion signals). Less is known about the role of these structures for human path integration. We tested path integration in patients who had undergone left or right medial temporal lobectomy as therapy for epilepsy. This procedure removed approximately 50 of the anterior portion of the hippocampus, as well as the amygdala and lateral temporal lobe. Participants attempted to walk without vision to a previously viewed target 26 m distant. Patients with right, but not left, hemisphere lesions exhibited both a decrease in the consistency of path integration and a systematic underregistration of linear displacement (and/or velocity) during walking. Moreover, the deficits were observable even when there were virtually no angular acceleration vestibular signals. The results suggest that structures in the medial temporal lobe participate in human path integration when individuals walk along linear paths and that this is so to a greater extent in right hemisphere structures than left. This information is relevant for future research investigating the neural substrates of navigation, not only in humans (e.g., functional neuroimaging and neuropsychological studies), but also in rodents and other animals.

Lateralization of brain activation to imagination and smell of odors using functional magnetic resonance imaging (fMRI): left hemispheric localization of pleasant and right hemispheric localization of unpleasant odors.

Purpose Our goal was to use functional MRI (fMRI) of brain to reveal activation in each cerebral hemisphere in response to imagination and smell of odors. Method FMRI brain scans were obtained in 24 normal subjects using multislice fast low angle shot (FLASH) MRI in response to imagination of banana and peppermint odors and in response to smell of corresponding odors of amyl acetate and menthone, respectively, and of pyridine. Three coronal sections selected from anterior to posterior brain regions were used. Similar studies were obtained in two patients with hyposmia using FLASH MRI and in one patient with hyposmia using echo planar imaging (EPI) both before and after theophylline treatment that returned smell function to or toward normal in each patient and in two patients with birhinal phantosmia (persistent foul odor) and global phantogeusia (persistent foul taste) with FLASH and EPI fMRI before and after treatment with neuroleptic drugs that inhibited their phantosmia and phantogeusia. Activation images were derived using correlation analysis. Ratios of hemispheric areas of brain activation to total hemispheric brain areas were calculated for FLASH fMRI, and numerical counts of pixel clusters in each hemisphere were made for EPI studies. Total pixel cluster counts in localized regions of each hemispheric section were also obtained. Results In normal subjects, activation generally occurred in left (L) > right (R) brain hemisphere in response to banana and peppermint odor imagination and to smell of corresponding odors of amyl acetate and menthone. Whereas there were no overall hemispheric differences for pyridine odor, activation in men was R > L hemisphere. Although absolute activation in both L and R hemispheres in response to banana odor imagination and amyl acetate smell was men > women, the ratio of L to R activation was women > men. In hyposmic patients studied by FLASH fMRI, activation to banana odor imagination and amyl acetate smell was L > R hemisphere both before and after theophylline treatment. In the hyposmic patient studied with EPI before theophylline treatment, activation to banana and peppermint odor imagination and to amyl acetate, menthone, and pyridine smell was R > L hemisphere; after theophylline treatment restored normal smell function, activation shifted completely with banana and peppermint odor imagination and amyl acetate and menthone smell to L > R hemisphere, consistent with responses in normal subjects. However, this shift also occurred for pyridine smell, which is opposite to responses in normal control subjects. In patients with phantosmia and phantogeusia, activation to phantosmia and phantogeusia before treatment was R > L hemisphere; after treatment inhibited phantosmia and phantogeusia, activation shifted with a slight L > R hemispheric lateralization. Localization of all lateralized responses indicated that anterior frontal and temporal cortices were brain regions most involved with imagination and smell of odors and with phantosmia and phantogeusia presence. Conclusion Imagination and smell of odors perceived as pleasant generally activated the dominant or L > R brain hemisphere. Smell of odors perceived as unpleasant and unpleasant phantosmia and phantogeusia generally activated the contralateral or R > L brain hemisphere. With remission of phantosmia and phantogeusia, hemispheric activation was not only inhibited, but also there was a slight shift to L > R hemispheric predominance. Predominant L > R hemispheric differences in brain activation in normal subjects occurred in the order amyl acetate > menthone > pyridine, consistent with the hypothesis that pleasant odors are more appreciated in L hemisphere and unpleasant odors more in R hemisphere. Anterior frontal and temporal cortex regions previously found activated by imagination and smell of odors and phantosmia and phantogeusia perception accounted for most hemispheric differences.

Taste and smell function in chronic disease:: A review of clinical and biochemical evaluations of taste and smell dysfunction in over 5000 patients at The Taste and Smell Clinic in Washington, DC

PURPOSE To describe systematic methods developed over 40 years among over 5000 patients at The Taste and Smell Clinic in Washington, DC to evaluate taste and smell dysfunction. MATERIALS AND METHODS A tripartite methodology was developed. First, methods to determine clinical pathology underlying the multiple disease processes responsible for taste and smell dysfunction were developed. Second, methods to determine biochemical parameters responsible for these pathologies were developed. Third, methods to implement these techniques were developed to form a unified basis upon which treatment strategies can be developed to treat these patients. RESULTS Studies were performed in 5183 patients. Taste loss was present in 62% of patients, smell loss in 87%. Most patients with taste loss (52%) exhibited Type II hypogeusia; most patients with smell loss (56%) exhibited Type II hyposmia. Sensory distortions were present in 60%. Four common diagnostic entities were found: post influenza-type hyposmia and hypogeusia (27% of patients), idiopathic causes (16%), allergic rhinitis (15%) and post head injury (14%). Regardless of clinical diagnosis the major biochemical abnormality found in most patients (~70%) was diminished parotid salivary and nasal mucus secretion of cAMP and cGMP. CONCLUSIONS Taste and smell dysfunctions are common clinical problems associated with chronic disease processes. These symptoms require a systematic, integrated approach to understand their multiple and complex components. The approach presented here can and has led to effective treatment.

Taste and smell phantoms revealed by brain functional MRI (fMRI).

PURPOSE Our goal was to demonstrate the appearance of phantom tastes and smells (phantageusia and phantosmia, respectively) by use of functional MRI (fMRI) of the brain and to demonstrate the efficacy of drug treatment that inhibited both the subjective presence of these phantoms and the fMRI brain activation initiated by these phantoms. METHOD Multislice FLASH MR or echo planar MR brain scans were obtained in two patients with phantageusia and phantosmia in response to memory of two tastants (salt and sweet); memory of two odors (banana and peppermint); actual smell of amyl acetate, menthone, and pyridine; and memory of phantom tastes and smells before and after treatment with thioridazine and haloperidol. Activation images were derived using correlation analysis, and ratios of brain area activated to total brain area were obtained. RESULTS Prior to treatment, both patients experienced persistent birhinal and global oral obnoxious tastes and smells in the absence of any external stimulus. The fMRI response to memory of phantoms was activation in sensory-specific brain regions for taste and smell, respectively. fMRI activation was greater than for memory of any tastant or odorant or for actual smell of any odor. After treatment with thioridazine or haloperidol, which successfully inhibited each phantom in each patient, fMRI response to phantom memory was significantly inhibited and was significantly lower than for memory of any tastant or odorant or actual smell of any odorant. CONCLUSION These results demonstrate that (a) phantom taste and smell can be revealed by fMRI brain activation, (b) brain activation in response to taste and smell phantoms is localized in sensory-specific brain regions for taste and smell, respectively, (c) brain activation in response to memory of each phantom initiated the greatest degree of activation we had previously measured, and (d) treatment with thioridazine or haloperidol inhibited both the presence of each phantom and its associated fMRI brain activation. This is the first study in which phantom tastes and smells have been demonstrated by an objective technique and treatment that inhibited the phantoms was characterized by objective inhibition of fMRI activation. These two patients represent a relatively common group that may be classified as having primary phantageusia and phantosmia distinct from those with phantoms or auras secondary to neurological, migrainous, psychiatric, or other causes.

Functional MRI of congenital hyposmia: brain activation to odors and imagination of odors and tastes.

Purpose Our goal was to use functional MRI (fMRI) to define brain activation in response to odors and imagination (“memory”) of odors and tastes in patients who never recognized odors (congenital hyposmia). Method Functional MR brain scans were obtained in nine patients with congenital hyposmia using multislice echo planar imaging (EPI) in response to odors of amyl acetate, menthone, and pyridine and to imagination (“memory”) of banana and peppermint odors and to salt and sweet tastes. Functional MR brain scans were compared with those in normal subjects and patients with acquired hyposmia. Activation images were derived using correlation analysis, and ratios of areas of brain activated to total and hemispheric brain areas were calculated. Total and hemispheric activated pixel counts were used to quantitate regional brain activation. Results Brain activation in response to odors was present in patients with congenital hyposmia. Activation was significantly lower than in normal subjects and patients with acquired hyposmia and did not demonstrate differential vapor pressure-dependent detection responsiveness or odor response lateralization. Regional activation localization was in anterior frontal and temporal cortex similar to that in normal subjects and patients with acquired hyposmia. Activation in response to presented odors was diverse, with a larger group exhibiting little or no activation with localization only in anterior frontal and temporal cortex and a smaller group exhibiting greater activation with localization extending to more complex olfactory integration sites. “Memory” of odors and tastes elicited activation in the same central nervous system (CNS) regions in which activation in response to presented odors occurred, but responses were significantly lower than in normal subjects and patients with acquired hyposmia and did not lateralize. Conclusion Odors induced CNS activation in patients with congenital hyposmia, which distinguishes olfaction from vision and audition since neither light nor acoustic stimuli induce CNS activation. Odor activation localized to anterior frontal and temporal cortex, consistent with the hypothesis that olfactory pathways are hard-wired into the CNS and that further pathways are undeveloped with primary olfactory system CNS connections but lack of secondary connections. However, some patients exhibited greater odor activation with response localization extending to cingulate and opercular cortex, indicating some olfactory signals impinge on and maintain secondary connections consistent with similar functions in vision and audition. Activation localization of taste “memory” to anterior frontal and temporal cortex is consistent with CNS plasticity and cross-modal CNS reorganization as described for vision and audition. Thus, there are differences and similarities between olfaction, vision, and audition, the differences dependent on unique qualities of olfaction, perhaps due to its diffuse, primitive, fundamental role in survival. Response heterogeneity to odors may reflect heterogeneous genetic abnormalities, independent of anatomic or hormonal changes but dependent on molecular abnormalities in growth factor function interfering with growth factor/stem cell interactions. Patients with congenital hyposmia offer an unique model system not previously explored in which congenital smell lack as measured by fMRI is reflective of congenital dysfunction of a major sensory system.