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1.  A Positron Tomographic Emission Study of Olfactory Induced Emotional Recall in Veterans with and without Combat-related Posttraumatic Stress Disorder 
Psychopharmacology bulletin  2007;40(1):8-30.
Memory for odors is often associated with highly emotional experiences, and odors have long been noted by clinicians to be precipitants of trauma symptoms in PTSD. Primitive brain systems involved in fear responsivity and survival also mediate smell, including the olfactory cortex and amygdala. The purpose of this study was to measure neural correlates of olfaction in PTSD.
We exposed male combat veterans with PTSD (N=8) and without PTSD (N=8) to a set of smells, including diesel (related to traumatic memories of combat), and three other types of smells: odorless air, vanilla/coconut and hydrogen sulfide (H2S) (resp. a neutral, positive, and negative hedonic non-traumatic smell) in conjunction with PET imaging of cerebral blood flow and assessment of psychophysiological and behavioral symptoms. All subjects also underwent a baseline of olfactory acuity.
PTSD patients rated diesel as unpleasant and distressing, resulting in increased PTSD symptoms and anxiety in PTSD versus combat controls. Exposure to diesel resulted in an increase in regional blood flow (rCBF) in amygdala, insula, medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC), and decreased rCBF in lateral prefrontal cortex (lPFC) in PTSD in comparison to combat controls. Combat controls showed less rCBF changes on any smell, and did not show amygdala activation upon diesel exposure.
These data support the hypothesis that in PTSD trauma-related smells can serve as strong emotional reminders. The findings indicate the involvement of a neural circuitry that shares olfactory elements and memory processing regions when exposed to trauma-related stimuli.
PMCID: PMC3236699  PMID: 17285093
PTSD; brain imaging techniques; olfaction; memory; amygdala
2.  Regional Cerebral Blood-Flow with 99mTc-ECD Brain Perfusion SPECT in Landau-Kleffner Syndrome: Report of Two Cases 
Case Reports in Radiology  2014;2014:617343.
Landau-Kleffner syndrome (LKS) is a rare childhood disorder characterized by acquired aphasia and epilepsy. 99mTc-ECD SPECT imaging was performed in two right-handed children with LKS. A relative decrease in perfusion was found in the left frontal-temporal cortices of both patients as well as in the left and right parietal cortices of one patient with aphasia, without clinical epilepsy. The degree of regional cerebral perfusion impairment did not correlate with the severity of the clinical and EEG abnormalities, but the area of hypoperfusion was compatible with the speech area of the brain. Overall, although asymmetrical temporoparietal perfusion appears as a common finding in LKS, SPECT findings in LKS alone cannot elucidate the pathogenic features of the disorder in the brain. Here, we present two cases of LKS in which we investigated SPECT perfusion scans.
PMCID: PMC4020496  PMID: 24868479
3.  Right Orbitofrontal Cortex Mediates Conscious Olfactory Perception 
Psychological science  2010;21(10):1454-1463.
Understanding how the human brain translates sensory impressions into conscious percepts is a key challenge of neuroscience research. Work in this area has overwhelmingly centered on the conscious experience of vision at the exclusion of the other senses—in particular, smell. We hypothesized that the orbitofrontal cortex (OFC) is a central substrate for olfactory conscious experience because of its privileged physiological role in odor processing. Combining functional magnetic resonance imaging, peripheral autonomic recordings, and olfactory psychophysics, we studied a case of complete anosmia (smell loss) in a patient with circumscribed traumatic brain injury to the right OFC. Despite a complete absence of conscious olfaction, the patient exhibited robust “blind smell,” as indexed by reliable odor-evoked neural activity in the left OFC and normal autonomic responses to odor hedonics during presentation of stimuli to the left nostril. These data highlight the right OFC’s critical role in subserving human olfactory consciousness.
PMCID: PMC3627397  PMID: 20817780
olfactory perception; consciousness; orbitofrontal cortex; lesion
4.  Comparison of Classical and Clozapine Treatment on Schizophrenia Using Positive and Negative Syndrome Scale of Schizophrenia (PANSS) and SPECT Imaging 
Many neuroimaging studies of schizophrenia have shown abnormalities in the frontal cortex, limbic system, basal ganglia, temporal and parietal lobes. These findings are not specific or consistent enough to build up a coherent theory of the origin of the brain abnormality in schizophrenia. This paper describes a state-of-the-art approach of SPECT to correlate neuropsychological evaluation. PANSS scores and different brain focal abnormalities of two groups of patients receiving Clozapine and classical antipsychotic treatments were observed. A total of 20 drug-free patients, actively psychotic schizophrenic, were selected according to the DSM-IV criteria. Pre-Post-treatment was designed using PANSS and 99mTc- ECD-SPECT to assess regional Cerebral Blood Flow (rCBF). The results showed that after treatment, differences in PANSS scores were significant in both groups, with superior scores resulting from the Clozapine therapy. Results were supported by SPECT, which showed a greater improvement in the Clozapine group. Both positive and negative symptoms were improved with Clozapine as well. Before treatment, hypofrontality was the most common (85%) finding, whereas after treatment hypofrontality was mostly cleared. However, in some areas like temporal and caudate, hyperfrontality was induced. Negative symptoms showed linkage to hypofrontality in both groups before and after treatment, and both positive and negative symptoms were improved more with Clozapine therapy than with classical treatment.
PMCID: PMC1145138  PMID: 15968344
Schizophrenia; SPECT imaging; PANSS scores
5.  Functional Neuro-Imaging and Post-Traumatic Olfactory Impairment 
To evaluate via a research literature survey the anterior neurological significance of decreased olfactory functioning following traumatic brain injuries.
Materials and Methods:
A computer literature review was performed to locate all functional neuro-imaging studies on patients with post-traumatic anosmia and other olfactory deficits.
A convergence of findings from nine functional neuro-imaging studies indicating evidence for reduced metabolic activity at rest or relative hypo-perfusion during olfactory activations. Hypo-activation of the prefrontal regions was apparent in all nine post-traumatic samples, with three samples yielding evidence of reduced activity in the temporal regions as well.
The practical ramifications include the reasonable hypothesis that a total anosmic head trauma patient likely has frontal lobe involvement.
PMCID: PMC3122553  PMID: 21716782
Anosmia; functional neuro-imaging; olfaction; traumatic brain injury
6.  Memory Networks in Tinnitus: A Functional Brain Image Study 
PLoS ONE  2014;9(2):e87839.
Tinnitus is characterized by the perception of sound in the absence of an external auditory stimulus. The network connectivity of auditory and non-auditory brain structures associated with emotion, memory and attention are functionally altered in debilitating tinnitus. Current studies suggest that tinnitus results from neuroplastic changes in the frontal and limbic temporal regions. The objective of this study was to use Single-Photon Emission Computed Tomography (SPECT) to evaluate changes in the cerebral blood flow in tinnitus patients with normal hearing compared with healthy controls. Methods: Twenty tinnitus patients with normal hearing and 17 healthy controls, matched for sex, age and years of education, were subjected to Single Photon Emission Computed Tomography using the radiotracer ethylenedicysteine diethyl ester, labeled with Technetium 99 m (99 mTc-ECD SPECT). The severity of tinnitus was assessed using the “Tinnitus Handicap Inventory” (THI). The images were processed and analyzed using “Statistical Parametric Mapping” (SPM8). Results: A significant increase in cerebral perfusion in the left parahippocampal gyrus (pFWE <0.05) was observed in patients with tinnitus compared with healthy controls. The average total THI score was 50.8+18.24, classified as moderate tinnitus. Conclusion: It was possible to identify significant changes in the limbic system of the brain perfusion in tinnitus patients with normal hearing, suggesting that central mechanisms, not specific to the auditory pathway, are involved in the pathophysiology of symptoms, even in the absence of clinically diagnosed peripheral changes.
PMCID: PMC3916334  PMID: 24516567
7.  99mTc HMPAO SPECT prediction of conversion from mild cognitive impairment to Alzheimer disease 
To examine the utility of single photon emission computed tomography (SPECT) to predict conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD).
Longitudinal, prospective study.
University-based memory disorders clinic.
127 patients with MCI and 59 healthy comparison subjects followed for 1 to 9 years.
Diagnostic evaluation, neuropsychological tests, social/cognitive function, olfactory identification, apolipoprotein E genotype, MRI, and brain 99mTc HMPAO SPECT scan with visual ratings and region of interest (ROI) analyses were done.
Visual ratings of SPECT temporal and parietal blood flow did not distinguish eventual MCI converters to AD (n=31) from non-converters (n=96) but the global rating predicted conversion (41.9% sensitivity and 82.3% specificity, Fisher's exact test p=0.013). Blood flow in each ROI was not predictive, but when dichotomized at the MCI patients' median value, low flow increased the hazard of conversion to AD for parietal (HR 2.96, 95%CI 1.16-7.53, p=0.023) and medial temporal regions (HR 3.12, 95%CI 1.14-8.56, p=0.027). In the 3-year follow-up sample, low parietal (p<0.05) and medial temporal (p<0.01) flow predicted conversion to AD, with or without controlling for age, MMSE, and apolipoprotein E ε4 genotype. These measures lost significance when other strong predictors were included in logistic regression analyses: verbal memory, social/cognitive functioning, olfactory identification deficits, hippocampal and entorhinal cortex volumes.
SPECT visual ratings showed limited utility in predicting MCI conversion to AD. The modest predictive utility of quantified low parietal and medial temporal flow using SPECT may decrease when other stronger predictors are available.
PMCID: PMC3103107  PMID: 20808143
Mild cognitive impairment; Alzheimer's disease; prediction; SPECT; clinical utility
8.  Hidden consequences of olfactory dysfunction: a patient report series 
The negative consequences of olfactory dysfunction for the quality of life are not widely appreciated and the condition is therefore often ignored or trivialized.
1,000 patients with olfactory dysfunction participated in an online study by submitting accounts of their subjective experiences of how they have been affected by their condition. In addition, they were given the chance to answer 43 specific questions about the consequences of their olfactory dysfunction.
Although there are less practical problems associated with impaired or distorted odor perception than with impairments in visual or auditory perception, many affected individuals report experiencing olfactory dysfunction as a debilitating condition. Smell loss-induced social isolation and smell loss-induced anhedonia can severely affect quality of life.
Olfactory dysfunction is a serious condition for those affected by it and it deserves more attention from doctors who treat affected patients as well as from scientist who research treatment options.
PMCID: PMC3733708  PMID: 23875929
Olfaction; Quality of life; Anosmia; Phantosmia; Parosmia; Anhedonia
9.  Differences at brain SPECT between depressed females with and without adult ADHD and healthy controls: etiological considerations 
Comorbidity between Attention Deficit Hyperactivity Disorder (ADHD) and mood disorders is common. Alterations of the cerebellum and frontal regions have been reported in neuro-imaging studies of ADHD and major depression.
Thirty chronically depressed adult females of whom 16 had scores below, and 14 scores above, cut-offs on the 25-items Wender Utah Retrospective Scale (WURS-25) and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) were divided into subgroups designated "Depression" and "Depression + ADHD", respectively. Twenty-one of the patients had some audiological symptom, tinnitus and/or hearing impairment. The patients were investigated with other rating scales and 99mTc-HMPAO SPECT. Controls for 99mTc-HMPAO SPECT were 16 healthy females. SPECT was analyzed by both statistical parametric mapping (SPM2) and the computerized brain atlas (CBA). Discriminant analysis was performed on the volumes of interest generated by the CBA, and on the scores from rating scales with the highest group differences.
The mean score of a depression rating scale (MADRS-S) was significantly lower in the "Depression" subgroup compared to in the "Depression + ADHD" subgroup. There was significantly decreased tracer uptake within the bilateral cerebellum at both SPM and CBA in the "Depression + ADHD" subgroup compared to in the controls. No decrease of cerebellar tracer uptake was observed in "Depression". Significantly increased tracer uptake was found at SPM within some bilateral frontal regions (Brodmann areas 8, 9, 10, 32) in the "Depression + ADHD" subgroup compared to in "Depression". An accuracy of 100% was obtained for the discrimination between the patient groups when thalamic uptake was used in the analysis along with scores from Socialization and Impulsivity scales.
The findings confirm the previous observation of a cerebellar involvement in ADHD. Higher bilateral frontal 99mTc-HMPAO uptake in "Depression + ADHD" compared to in "Depression" indicate a difference between these subgroups. 99mTc-HMPAO uptake mechanisms are discussed.
PMCID: PMC2753339  PMID: 19723308
10.  A cortical pathway to olfactory naming: evidence from primary progressive aphasia 
Brain  2013;136(4):1245-1259.
It is notoriously difficult to name odours. Without the benefit of non-olfactory information, even common household smells elude our ability to name them. The neuroscientific basis for this olfactory language ‘deficit’ is poorly understood, and even basic models to explain how odour inputs gain access to transmodal representations required for naming have not been put forward. This study used patients with primary progressive aphasia, a clinical dementia syndrome characterized by primary deficits in language, to investigate the interactions between olfactory inputs and lexical access by assessing behavioural performance of olfactory knowledge and its relationship to brain atrophy. We specifically hypothesized that the temporal pole would play a key role in linking odour object representations to transmodal networks, given its anatomical proximity to olfactory and visual object processing areas. Behaviourally, patients with primary progressive aphasia with non-semantic subtypes were severely impaired on an odour naming task, in comparison with an age-matched control group. However, with the availability of picture cues or word cues, odour matching performance approached control levels, demonstrating an inability to retrieve but not to recognize the name and nature of the odorant. The magnitude of cortical thinning in the temporal pole was found to correlate with reductions in odour familiarity and odour matching to visual cues, whereas the inferior frontal gyrus correlated with both odour naming and matching. Volumetric changes in the mediodorsal thalamus correlated with the proportion of categorical mismatch errors, indicating a possible role of this region in error-signal monitoring to optimize recognition of associations linked to the odour. A complementary analysis of patients with the semantic subtype of primary progressive aphasia, which is associated with marked temporopolar atrophy, revealed much more pronounced impairments of odour naming and matching. In identifying the critical role of the temporal pole and inferior frontal gyrus in transmodal linking and verbalization of olfactory objects, our findings provide a new neurobiological foundation for understanding why even common odours are hard to name.
PMCID: PMC3613711  PMID: 23471695
olfaction; odour object knowledge; recognition; naming; language; semantics; temporal pole; inferior frontal gyrus; primary progressive aphasia; human brain; MRI
11.  Olfactory Examination in Korsakoff's Syndrome: Implications for Early Diagnosis 
ISRN Otolaryngology  2011;2011:506167.
Whilst olfactory dysfunction has been reported in Korsakoff's Syndrome (KS) patients, the diagnostic implications of this have not been fully explored. KS can be difficult to diagnose because cognitive symptoms are similar to other diagnoses. For instance, patients with Frontal Lobe (FL) Syndrome may present with memory impairments that are similar to KS. Participants were given the Benton Visual Retention Test-Fifth Edition (BVRT-V), to identify working memory dysfunction, and a Brief Smell Identification Test (B-SIT), to evaluate olfactory function. B-SIT scores were found to be significantly lower in the KS group compared to the control and FL groups. In contrast, the error scores on the BVRT-V were significantly higher in both the KS and FL groups compared to the healthy control subjects. Therefore, we suggest that olfactory function may aid in the differential diagnosis of patients presenting with working memory dysfunction.
PMCID: PMC3658704  PMID: 23724253
What pattern of brain damage could completely obliterate the sense of olfaction in humans? We had an opportunity to address this intriguing question in patient B., who has extensive bilateral damage to most of the limbic system, including the medial and lateral temporal lobes, orbital frontal cortex, insular cortex, anterior cingulate cortex, and basal forebrain, caused by herpes simplex encephalitis. The patient demonstrated profound impairments in odor identification and recognition. Moreover, he could not discriminate between olfactory stimuli and he had severe impairments in odor detection. Reliable stimulus detection was obtained only for solutions of the organic solvent acetone and highly concentrated solutions of ethanol. In contrast to the more circumscribed olfactory deficits demonstrated in patients with damage confined to either the temporal lobes or orbitofrontal cortex (which tend to involve odor identification but not odor detection), patient B. demonstrates a strikingly severe and complete anosmia. This contrast in olfactory abilities and deficits as a result of different anatomical pathology affords new insights into the neural substrates of olfactory processing in humans.
PMCID: PMC3269190  PMID: 22220560
13.  PET and SPECT in whiplash syndrome: a new approach to a forgotten brain? 
Whiplash associated disorders are a medicolegally controversial condition becoming increasingly worrisome in the western world. This study was designed to evaluate perfusion and glucose metabolism in whiplash brain. Using Tc-99m-bicisate (ECD) single photon emission computed tomography (SPECT) and F-18-fluorodeoxyglucose (FDG) PET, six clinically and neuropsychologically controlled patients (patient group) with whiplash syndrome and 12 normal controls (control group) were investigated. Standardised elliptical regions of interest (ROIs) were determined in three adjacent transaxial slices in the frontal, parietal, temporal, and parieto-occipital cortex, cerebellum, brain stem, basal ganglia, and thalamus. For PET, the glucose metabolic index (GMI; =ROI uptake/global uptake at the level of the basal ganglia) and, for SPECT, the perfusion index (PI; =ROI/global) were calculated. In the patient group there was significant hypometabolism and hypoperfusion in the parieto-occipital regions (on the right (R) and left (L) side) compared with the control group: PET data: GMI parieto-occipital R: control 1.066 (0.081) (mean (SD)), patient 0.946 (0.065); P=0.0092, Mann Whitney. GMI parieto-occipital L: control 1.034 (0.051), patient 0.922 (0.073); p=0.0067. SPECT data: PI parieto-occipital R: control 1.262 (0.066), patient 1.102 (0.063); P=0.0039. PI parieto-occipital L: control 1.226 (0.095), patient 1.098 (0.075); P=0.0273. In some patients there was hypometabolism (>2 SD of control) in regions other than the parieto-occipital region. It is hypothesised that parieto-occipital hypometabolism may be caused by activation of nociceptive afferent nerves from the upper cervical spine.

PMCID: PMC2169690  PMID: 9328255
14.  Evaluation of both perfusion and atrophy in multiple system atrophy of the cerebellar type using brain SPECT alone 
BMC Medical Imaging  2010;10:17.
Partial volume effects in atrophied areas should be taken into account when interpreting brain perfusion single photon emission computed tomography (SPECT) images of neurodegenerative diseases. To evaluate both perfusion and atrophy using brain SPECT alone, we developed a new technique applying tensor-based morphometry (TBM) to SPECT.
After linear spatial normalization of brain perfusion SPECT using 99mTc-ethyl cysteinate dimer (99mTc-ECD) to a Talairach space, high-dimension-warping was done using an original 99mTc-ECD template. Contraction map images calculated from Jacobian determinants and spatially normalized SPECT images using this high-dimension-warping were compared using statistical parametric mapping (SPM2) between two groups of 16 multiple system atrophy of the cerebellar type (MSA-C) patients and 73 age-matched normal controls. This comparison was also performed in conventionally warped SPECT images.
SPM2 demonstrated statistically significant contraction indicating local atrophy and decreased perfusion in the whole cerebellum and pons of MSA-C patients as compared to normal controls. Higher significance for decreased perfusion in these areas was obtained in high-dimension-warping than in conventional warping, possibly due to sufficient spatial normalization to a 99mTc-ECD template in high-dimensional warping of severely atrophied cerebellum and pons. In the present high-dimension-warping, modification of tracer activity remained within 3% of the original tracer distribution.
The present new technique applying TBM to brain SPECT provides information on both perfusion and atrophy at the same time thereby enhancing the role of brain perfusion SPECT
PMCID: PMC2927477  PMID: 20701753
15.  Cortical inhibition deficits in recent onset PTSD after a single prolonged trauma exposure☆ 
NeuroImage : Clinical  2013;3:226-233.
A variety of structural abnormalities have been described in post traumatic stress disorder (PTSD), but only a few studies have focused on cortical thickness alterations in recent onset PTSD. In this study, we adopted surface-based morphometry (SBM), which enables an exploration of global structural changes throughout the brain, in order to compare cortical thickness alterations in recent onset PTSD patients, trauma-exposed subjects but without PTSD, and normal controls. Moreover, we used region of interest (ROI) partial correlation analysis to evaluate the correlation among PTSD symptom severity and significant changes of cortical thickness. The widespread cortical thickness reduction relative to the normal controls were found in bilateral inferior and superior parietal lobes, frontal lobes, hippocampus, cingulate cortex, and right lateral occipital lobes in trauma survivors, whereas cortical thickness was only increased in left calcarine cortex in PTSD group. The average cortical thickness of hippocampus and cingulate cortex decreased by 10.75% and 9.09% in PTSD, 3.48% and 2.86% in non PTSD. We further demonstrated that the cortical thicknesses of bilateral ACC and PCC, superior frontal lobes, and hippocampus are negatively correlated with CAPS scores in all trauma survivors. Our study results suggest that stress widens cortical thinning regions and causes more serious effect in recent onset PTSD than non PTSD. It also shows that the cortical thinning in recent onset PTSD predicts the symptom severity.
•PTSD caused by rare, severe disaster (69 miners trapped in 1.4 km underground for 75 h).•The surface-based morphometry is based on such serious, sustained and acute trauma.•The comparisons are among healthy, survivors with, and without recent onset PTSD.•Hippocampus and cingulate thickness in PTSD decreased 3 times than non PTSD.•The altered regions in PTSD group are negatively correlated with CAPS scores.
PMCID: PMC3815016  PMID: 24273707
Recent onset PTSD; Cortical thickness; Surface-based morphometry
16.  Alleviation of Brain Hypoperfusion after Preventative Treatment with Lomerizine in an Elderly Migraineur with Aura 
Previous studies of brain single-photon emission tomography (SPECT) showed changes of regional cerebral blood flow (rCBF) in migraineurs during prodromes or headache attacks. Little is known about how successful medication of migraine prevention can reflect rCBF in migraineurs. We highlighted alternation of brain SPECT findings in a migraineur with aura before and after prophylactic treatment with lomerizine, a calcium channel blocker. A 70-year-old man with migraine developed visual disturbance frequently at walking exercise for the recent 3 months. After this visual attack, a mild-degree of throbbing headache occured occasionally. Brain SPECT using 99mTc-ethyl cysteinate dimer was performed at interictal time of migraine. Brain SPECT before lomerizine treatment revealed hypoperfusion in the frontal, parietal, and occipital regions. He was diagnosed with recurrence of migraine with aura (MA). Lomerizine (10 mg/day, po) was administered for 3 months. MA and visual aura without headache were dramatically improved. Migraine attacks and visual disturbance were not induced at exercise. At 3 months after lomerizine medication, brain SPECT showed remarkable increase of rCBF. These SPECT changes of our patient indicated that antimigraine mechanism of lomerizine could contribute to restoration of cerebral hypoperfusion.
PMCID: PMC3065840  PMID: 21490733
17.  Efficacy of 99mTc-EDDA/HYNIC-TOC SPECT/CT scintigraphy in Graves’ ophthalmopathy 
The aim of this study was to investigate the predictive role of the orbital somatostatin receptor scintigraphy with 99mTc-EDDA/HYNIC-TOC (99mTc-TOC) to detect clinical stage of Graves’ ophthalmopathy and the response to corticosteroid therapy. The subjects of the experiment were 46 patients with Graves’ ophthalmopathy (GO) and four volunteers without eye disease or GO as the normal group (NG). Single photon emission computed tomography (SPECT), computed tomography (CT) and the left and right lateral position planar imaging of the heads of the all subjects were obtained 4 h after the intravenous injection of 555 MBq of 99mTc-TOC. The 99mTc-TOC SPECT/CT was repeated 3 months later. 35 (35/46) patients were received corticosteroid therapy (prednisolone, 10 mg po tid ) for 3 months, however, the other 11 patients as control groups did not receive any treatment. The treatment effect was evaluated both by the orbital 99mTc-TOC uptake and NOSPECS. A significant decrease in the O/OC ratio was observed in 22 GO patients between pre- and post-treatment (1.64 ± 0.13 vs. 1.21 ± 0.09, P < 0.05). There were neither significant difference of the O/OC ratio in 13 GO patients between pre- and post-treatment periods, nor significant difference in the 9 (9/11) patients before and after three months. Orbital 99mTc-TOC scintigraphy is a feasible technique to estimate the Graves’ ophthalmopathy activity and predict the response to subsequent corticosteroid therapy in GO patients. The technique could be a useful tool for physicians not familiar with CAS determination.
PMCID: PMC3477727  PMID: 23133815
Graves’ ophthalmopathy; single photon emission computed tomography (SPECT); somatostatin receptor; 99mTc-TOC
18.  A SPECT Imaging Study Of Driving Impairment In Patients With Alzheimer's Disease 
Single photon emission computed tomography (SPECT) was used in this study to examine the neurophysiologic basis of driving impairment in 79 subjects with dementia. Driving impairment, as measured by caregiver ratings, was significantly related to regional reduction of right hemisphere cortical perfusion on SPECT, particularly in the temporo-occipital area. With increased severity of driving impairment, frontal cortical perfusion was also reduced. Clock drawing was more significantly related to driving impairment than the Mini-Mental State Examination. Driving impairment in Alzheimer's disease is related to changes in cortical function which vary according to severity of disease. Cognitive tests of visuoperceptual and executive functions may be more useful screening tools for identifying those at greatest risk for driving problems than examinations like the Mini-Mental State Examination, that are weighted toward left hemisphere based verbal tasks.
PMCID: PMC3292192  PMID: 10765046
SPECT; driving; Alzheimer's disease; dementia
19.  SPECT, MRI and cognitive functions in multiple sclerosis. 
Seventeen patients with relapsing remitting multiple sclerosis (MS) and mild physical disability had neuropsychological testing, magnetic resonance imaging (MRI) and single photon emission computerised tomography (SPECT) using technetium 99m (99mTc) hexamethyl-propyleneamine oxime (HMPAO). Performance in verbal fluency, naming and memory testing appeared to be impaired in MS patients compared with 17 age-sex and education matched normal controls. Weighted periventricular and confluent lesion scores and the width of the third ventricle, proved to be the most sensitive MRI measures in differentiating more cognitively impaired patients from those who were relatively unimpaired. Ratios of regional to whole brain activity, measured by SPECT, showed significant reduction in the frontal lobes and in the left temporal lobe of MS patients. A relationship was found between left temporal abnormality in 99mTc-HMPAO uptake and deficit in verbal fluency and verbal memory. Finally, asymmetrical lobar activity indicated a predominant left rather than right temporo-parietal involvement.
PMCID: PMC1014343  PMID: 2019835
20.  Cellular and Behavioral Effects of Cranial Irradiation of the Subventricular Zone in Adult Mice 
PLoS ONE  2009;4(9):e7017.
In mammals, new neurons are added to the olfactory bulb (OB) throughout life. Most of these new neurons, granule and periglomerular cells originate from the subventricular zone (SVZ) lining the lateral ventricles and migrate via the rostral migratory stream toward the OB. Thousands of new neurons appear each day, but the function of this ongoing neurogenesis remains unclear.
Methodology/Principal Findings
In this study, we irradiated adult mice to impair constitutive OB neurogenesis, and explored the functional impacts of this irradiation on the sense of smell. We found that focal irradiation of the SVZ greatly decreased the rate of production of new OB neurons, leaving other brain areas intact. This effect persisted for up to seven months after exposure to 15 Gray. Despite this robust impairment, the thresholds for detecting pure odorant molecules and short-term olfactory memory were not affected by irradiation. Similarly, the ability to distinguish between odorant molecules and the odorant-guided social behavior of irradiated mice were not affected by the decrease in the number of new neurons. Only long-term olfactory memory was found to be sensitive to SVZ irradiation.
These findings suggest that the continuous production of adult-generated neurons is involved in consolidating or restituting long-lasting olfactory traces.
PMCID: PMC2737283  PMID: 19753118
21.  Recovery of olfactory function after nine years of post-traumatic anosmia: a case report 
Olfactory loss due to head trauma is a common condition. Depending on the severity of the head trauma, anosmia might occur in up to 30% of patients. The period of time until recovery has been reported to be a couple of months in most cases. However, recovery from post-traumatic olfactory loss might occur much later. We present a rare case of recovery from anosmia nine years after the initial trauma.
Case presentation
We report the case of a 54-year-old Caucasian man who suffered complete anosmia from a severe car accident. Smell function as well as flavor perception during eating and drinking were also completely lost. After nine years, the patient had his first olfactory impressions, with his sense of smell gradually improving over a period of three years. We confirmed recovery of olfactory function using psychophysical and electrophysiological techniques.
In most cases, recovery of smell function occurs relatively soon after the head trauma and seems to rarely occur more than two years after the incident. However, patients should be informed that there is a small chance of recovery a long time after the trauma.
PMCID: PMC2767158  PMID: 19918296
22.  Longitudinal Changes in Cortical Thickness in Children after Traumatic Brain Injury and their Relation to Behavioral Regulation and Emotional Control 
The purpose of this study was to assess patterns of cortical development over time in children who had sustained traumatic brain injury (TBI) as compared to children with orthopedic injury (OI), and to examine how these patterns related to emotional control and behavioral dysregulation, two common post-TBI symptoms. Cortical thickness was measured at approximately 3 and 18 months post-injury in 20 children aged 8.2 to 17.5 years who had sustained moderate-to-severe closed head injury and 21 children aged 7.4 to 16.7 years who had sustained OI. At approximately 3 months post-injury, the TBI group evidenced decreased cortical thickness bilaterally in aspects of the superior frontal, dorsolateral frontal, orbital frontal, and anterior cingulate regions compared to the control cohort, areas of anticipated vulnerability to TBI-induced change. At 18 months post-injury, some of the regions previously evident at 3 months post-injury remained significantly decreased in the TBI group, including bilateral frontal, fusiform, and lingual regions. Additional regions of significant cortical thinning emerged at this time interval (bilateral frontal regions and fusiform gyrus and left parietal regions). However, differences in other regions appeared attenuated (no longer areas of significant cortical thinning) by 18 months post-injury including large bilateral regions of the medial aspects of the frontal lobes and anterior cingulate. Cortical thinning within the OI group was evident over time in dorsolateral frontal and temporal regions bilaterally and aspects of the left medial frontal and precuneus, and right inferior parietal regions. Longitudinal analyses within the TBI group revealed decreases in cortical thickness over time in numerous aspects throughout the right and left cortical surface, but with notable “sparing” of the right and left frontal and temporal poles, the medial aspects of both the frontal lobes, the left fusiform gyrus, and the cingulate bilaterally. An analysis of longitudinal changes in cortical thickness over time (18 months – 3 months) in the TBI versus OI group demonstrated regions of relative cortical thinning in the TBI group in bilateral superior parietal and right paracentral regions, but relative cortical thickness increases in aspects of the medial orbital frontal lobes and bilateral cingulate and in the right lateral orbital frontal lobe. Finally, findings from analyses correlating the longitudinal cortical thickness changes in TBI with symptom report on the Emotional Control subscale of the Behavior Rating Inventory of Executive Function (BRIEF) demonstrated a region of significant correlation in the right medial frontal and right anterior cingulate gyrus. A region of significant correlation between the longitudinal cortical thickness changes in the TBI group and symptom report on the Behavioral Regulation Index was also seen in the medial aspect of the left frontal lobe.
Longitudinal analyses of cortical thickness highlight an important deviation from the expected pattern of developmental change in children and adolescents with TBI, particularly in the medial frontal lobes, where typical patterns of thinning fail to occur over time. Regions which fail to undergo expected cortical thinning in the medial aspects of the frontal lobes correlate with difficulties in emotional control and behavioral regulation, common problems for youth with TBI. Examination of post-TBI brain development in children may be critical to identification of children that may be at risk for persistent problems with executive functioning deficits and the development of interventions to address these issues.
PMCID: PMC3322311  PMID: 22266409
traumatic brain injury; child; imaging; volumetrics; longitudinal; behavior; emotion; frontal lobes; cortical thickness
23.  Functional brain abnormalities localized in 55 chronic tinnitus patients: fusion of SPECT coincidence imaging and MRI 
Tinnitus is often defined as the perception of sounds or noise in the absence of any external auditory stimuli. The pathophysiology of subjective idiopathic tinnitus remains unclear. The aim of this study was to investigate the functional brain activities and possible involved cerebral areas in subjective idiopathic tinnitus patients by means of single photon emission computerized tomography (SPECT) coincidence imaging, which was fused with magnetic resonance imaging (MRI). In this cross-sectional study, 56 patients (1 subject excluded) with subjective tinnitus and 8 healthy controls were enrolled. After intravenous injection of 5 mCi F18-FDG (fluorodeoxyglucose), all subjects underwent a brain SPECT coincidence scan, which was then superimposed on their MRIs. In the eight regions of interest (middle temporal, inferotemporal, medial temporal, lateral temporal, temporoparietal, frontal, frontoparietal, and parietal areas), the more pronounced values were represented in medial temporal, inferotemporal, and temporoparietal areas, which showed more important proportion of associative auditory cortices in functional attributions of tinnitus than primary auditory cortex. Brain coincidence SPECT scan, when fused on MRI is a valuable technique in the assessment of patients with tinnitus and could show the significant role of different regions of central nervous system in functional attributions of tinnitus.
PMCID: PMC2949154  PMID: 20068582
magnetic resonance imaging; SPECT coincidence imaging; tinnitus
24.  Abnormal regional cerebral blood flow on 99mTc ECD brain SPECT in patients with primary Sjögren's syndrome and normal findings on brain magnetic resonance imaging 
Annals of the Rheumatic Diseases  2002;61(9):774-778.
Objective: Technetium-99m ethyl cysteinate dimer (99mTc ECD) single photon emission computed tomography (SPECT) of the brain was used to detect abnormal regional cerebral blood flow (rCBF) in patients with primary Sjögren's syndrome (pSS) and normal findings on brain magnetic resonance imaging (MRI).
Methods: 99mTc ECD brain SPECT was performed to detect brain lesions showing hypoperfusion in 32 female patients with pSS and definite neuropsychiatric symptoms or signs. Seventeen female patients with pSS without neuropsychiatric symptoms and signs were included as a control group for comparison. All of the 49 patients with pSS had normal findings on brain MRI.
Results: 99mTc ECD brain SPECT showed brain regions with hypoperfusion in 18 (56.3%) of the 32 patients, and parietal lobes were the most common areas with such lesions. By contrast, 99mTc ECD brain SPECT showed brain regions with hypoperfusion in only three (17.6%) of the 17 patients with pSS without neuropsychiatric symptoms or signs.
Conclusion: This study suggests that 99mTc ECD SPECT is a sensitive tool for detecting regions of hypoperfusion in the brains of patients with pSS and neuropsychiatric symptoms or signs and normal findings on brain MRI. However, a review of the literature showed that the 99mTc ECD SPECT findings in patients with pSS were non-specific.
PMCID: PMC1754217  PMID: 12176800
25.  Olfactory Processing, Sex Effects and Heterogeneity in Schizophrenia 
Schizophrenia Research  2011;135(1-3):144-151.
Smell identification deficits are associated with negative symptoms in schizophrenia, particularly in males. Far less information is known about the relationship of odor detection sensitivity (acuity) and negative symptoms in schizophrenia, and currently there is a dearth in sex-stratified research specifically examining odor sensitivity and smell identification.
Fifty-eight individuals with schizophrenia and 42 healthy comparison subjects were assessed on tests of odor sensitivity, smell identification and cognition. Negative symptoms were assessed with the Positive and Negative Syndrome Scale and the Schedule for the Deficit Syndrome.
In healthy males, increased odor detection sensitivity predicted better smell identification scores. In contrast, male schizophrenia patients showed a significant inverse relationship, in which increased odor sensitivity predicted lower smell identification scores. Odor sensitivity and smell identification were unrelated in both schizophrenia and healthy females. Olfactory processing was strongly linked to negative symptoms, but the relationships differed by sex. Emotional expression deficits were related to odor detection hypersensitivity in female patients, whereas smell identification deficits predicted these emotional deficits in male cases.
Sex differences in olfactory functioning were identified in healthy subjects and in schizophrenia patients. Smell identification was related to negative symptoms in males with schizophrenia, whereas odor detection sensitivity predicted these features in females. Sex differences should be considered in future analyses that employ odor stimuli for neuropsychiatric research.
PMCID: PMC3288877  PMID: 22177347
Schizophrenia; sex differences; negative symptoms; odor sensitivity; smell identification

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