Olfactory testing: rules for odor identification

Neurology manuals generally recommend odor identification for simple assessment of olfaction. Nevertheless, even patients with normal olfaction (normosmics) often perform only poorly. Three experiments demonstrate that such an ambiguous outcome will disappear if the test incorporates highly familiar substances and, more important, a procedure to circumvent the olfactory-verbal gap that frequently separates an odor from its name. One multiple-choice procedure, for instance, led to 100% accuracy among normosmics. Another led to 99% accuracy among normosmics and 0% accuracy among anosmics. The investigation also reveals that scratch-and-sniff labels could possibly replace customary odorants in the clinical test.     

Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon4 status.

OBJECTIVE: To determine whether olfactory status predicts cognitive decline (CD) over a 2-year follow-up period. METHODS: The authors enrolled individuals in a community-based longitudinal study of memory and aging in the Japanese-American community in King County, WA, between 1992 and 1994. At baseline they screened 1,985 persons using the Cognitive Abilities Screening Instrument (CASI) and the 12-item Cross-Cultural Smell Identification Test (CC-SIT). Of these 1,985 people, 1,836 were found not to be demented. Two years later the authors rescreened 1,604 participants with the CASI. They defined CD as a 2-year loss of > or =5.15 points/100 on the CASI. They genotyped 69% of the 1,604 people completing both examinations for apolipoprotein E (apoE). RESULTS: After adjusting for age, CASI score at baseline, education, smoking, sex, and follow-up time, the authors determined an odds ratio (OR) for CD of 0.90 (95% CI, 0.84 to 0.97) for an increase in each correct point on the CC-SIT (range, 0 to 12). Compared with normosmics, the OR for persons with impaired olfaction (microsmics) was 1.25 (95% CI, 0.83 to 1.89) and for anosmics the OR was 1.92 (95% CI, 1.06 to 3.47). Persons who were anosmic at baseline and who had at least one APOE-epsilon4 allele had 4.9 times the risk of CD (95% CI, 1.6 to 14.9) compared with normosmics without the epsilon4 allele. The estimated relative risk among women was 9.7 (95% CI, 1.3 to 70.4), and for men the risk was 3.2 (95% CI, 0.8 to 12.6). Receiver operating characteristic (ROC) curves showed that although the area under the curve (AUC) for baseline CASI was only 0.51, the AUC for CC-SIT alone was 0.62. Adding CC-SIT to the ROC model with CASI improved the AUC curve from 0.51 to 0.62. CONCLUSIONS: Unexplained olfactory dysfunction in the presence of one or more APOE-epsilon4 alleles is associated with a high risk of cognitive decline. Cross-Cultural Smell Identification Test classifies people with cognitive decline correctly to a greater degree than a global cognitive test.     

Annual Number of Spinal Cord Stimulation Procedures Performed in the State of Florida During 2018: Implications for Establishing Neuromodulation Centers of Excellence

ObjectiveTo assess the volume of spinal cord stimulation procedures performed by physicians in the state of Florida in 2018.Materials and MethodsWe obtained information from publicly available state databases for all patients undergoing procedures in 2018 at Florida hospitals, hospital-owned facilities, and independent ambulatory surgery centers. Cases in which a spinal cord stimulation procedure was performed were identified. We estimated for each physician office-based spinal cord stimulation trials (not subject to state reporting) based on the published Florida conversion factor of 25.6% of the total number of such procedures. The medical specialty of the listed performing physician was determined based on the national provider identifier. Counts of neurostimulation procedures performed by physician and within specialties were determined. The numbers of physicians and specialties performing various thresholds between 1 and ≥100 per year were determined, and the percentages of patients whose care was delivered by physicians below each threshold were determined.ResultsThe data analyzed included 10,762 spinal cord stimulation cases. Among the 606 physicians who performed at least one spinal cord stimulation procedure, only nine performed at least 100 cases in 2018. During 2018, 78.4% of physicians performed, on average, <2 spinal cord stimulation procedures per month; there were 29.4% of spinal cord stimulation patients cared for by such physicians. Physicians performing less than four cases per month provided care for 56.9% of all cases.ConclusionsFew physicians performing spinal cord stimulation procedures in the state of Florida in 2018 would have been considered as "high volume.” Although volume is only one among many criteria used to designate centers of excellence for other procedures, the potential impact on physician practice and patient access to care should be considered if a specific minimum number of annual cases by physician is to be established.     

Involvement of the human ventrolateral thalamus in olfaction

It is widely assumed that the thalamus is not involved in olfaction. The ventrolateral thalamus is, however, closely connected to the contralateral cerebellum, which is involved in the sense of smell based on findings from functional imaging studies and findings of olfactory deficits in patients with cerebellar disease. We hypothesized that olfactory deficits following lesions of the ventrolateral thalamus may be similar to olfactory deficits following cerebellar lesions. Fifteen patients with a focal thalamic lesion involving the ventrolateral thalamus were examined and compared to 15 patients with a focal cerebellar lesion and 15 healthy controls. A detailed olfactory test (“Sniffin’ Sticks”) was used to assess different olfactory functions separately for each nostril. In the group of patients with a lesion of the ventrolateral thalamus, an impairment of the odor threshold was found at the ipsilateral nostril, consistent with the unilateral orientation of the olfactory system in the telencephalon. In the group of patients with a cerebellar lesion, an olfactory deficit at the contralesional nostril emerged. In controls, no significant side difference was found. The involvement of the ventrolateral thalamus in olfaction is comparable to that of the cerebellum in respect to odor threshold. Further study is needed to assess if these findings are related to an impairment of an olfactomotor loop. Present evidence for this hypothesis is indirect. Effects were subclinical as none of the patients reported olfactory disturbance. The results suggest that the cerebello-thalamic axis plays an adjuvant role in olfaction.     

The fundamental role of memory in olfactory perception

Current emphasis on odorant physiochemical features as the basis for perception largely ignores the synthetic and experience-dependent nature of olfaction. Olfaction is synthetic, as mammals have only limited ability to identify elements within even simple odor mixtures. Furthermore, olfaction is experience-bound, as exposure alone can significantly affect the extent to which stimuli can be discriminated. We propose that early analytical processing of odors is inaccessible at the behavioral level and that all odors are initially encoded as 'objects' in the piriform cortex. Moreover, we suggest that odor perception is wholly dependent on the integrity of this memory system and that its loss severely impairs normal perception.     

Effects of deep brain stimulation of the cerebellothalamic pathways on the sense of smell

The cerebellum and the motor thalamus, connected by cerebellothalamic pathways, are traditionally considered part of the motor-control system. Yet, functional imaging studies and clinical studies including patients with cerebellar disease suggest an involvement of the cerebellum in olfaction. Additionally, there are anecdotal clinical reports of olfactory disturbances elicited by electrical stimulation of the motor thalamus and its neighbouring subthalamic region. Deep brain stimulation (DBS) targeting the cerebellothalamic pathways is an effective treatment for essential tremor (ET), which also offers the possibility to explore the involvement of cerebellothalamic pathways in the sense of smell. This may be important for patient care given the increased use of DBS for the treatment of tremor disorders. Therefore, 21 none-medicated patients with ET treated with DBS (13 bilateral, 8 unilateral) were examined with “Sniffin' Sticks,” an established and reliable method for olfactory testing. Patients were studied either with DBS switched on and then off or in reversed order. DBS impaired odor threshold and, to a lesser extent, odor discrimination. These effects were sub-clinical as none of the patients reported changes in olfactory function. The findings, however, demonstrate that olfaction can be modulated in a circumscribed area of the posterior (sub-) thalamic region. We propose that the impairment of the odor threshold with DBS is related to effects on an olfacto-motor loop, while disturbed odor discrimination may be related to effects of DBS on short-term memory.     

Color–Odor Interactions: A Review and Model

Certain colors are seen as corresponding to, and thus appropriate to, certain odors (e.g., red for cherry odor). When colors accompany odors, our perceptions of the odors are changed. Appropriate colors often affect our perception of the odors differently from inappropriate colors. This paper discusses the literature on color–odor correspondences including possible causes of these correspondences. It then reviews findings on the influence of color on odor identification, odor discrimination, odor intensity, and odor pleasantness. Color's effect on both orthonasal and retronasal olfaction is discussed. A model for how color exerts its effects on odor is proposed.     

Olfactory Dysfunction as an Early Biomarker in Parkinson’s Disease

Olfactory dysfunction is common in Parkinson's disease(PD) and often predates the diagnosis by years,reflecting early deposition of Lewy pathology, the histologic hallmark of PD, in the olfactory bulb. Clinical tests are available that allow for the rapid characterization of olfactory dysfunction, including tests of odor identification,discrimination, detection, and recognition thresholds,memory, and tests assessing the build-up of odor intensity across increasing suprathreshold stimulus concentrations.The high prevalence of olfactory impairment, along with the ease and low cost of assessment, has fostered great interest in olfaction as a potential biomarker for PD.Hyposmia may help differentiate PD from other causes of parkinsonism, and may also aid in the identification of‘‘pre-motor' PD due to the early pathologic involvement of olfactory pathways. Olfactory function is also correlated with other non-motor features of PD and may serve as a predictor of cognitive decline. In this article, we summarize the existing literature on olfaction in PD, focusing on the potential for olfaction as a biomarker for early or differential diagnosis and prognosis.     

Extended testing across,not within,tasks raises diagnostic accuracy of smell testing in Parkinson's disease

The aim of this study was to determine whether extended olfactory testing within a single olfactory task and/or across olfactory tasks increases diagnostic accuracy of olfactory testing in Parkinson's disease (PD). Olfactory function was assessed using an extended version of the “Sniffin' Sticks”, comprising 32‐item odor identification and discrimination tasks, and a detection threshold task in 52 PD patients and 50 controls, all aged between 49 and 78 years. ROC curves based on sensitivity and specificity estimates were used to compare the diagnostic accuracy of extended and combined olfactory testing. There was no significant difference in diagnostic accuracy between the 16‐item and the 32‐item versions of the odor identification or discrimination test. The single olfactory test that was best in discriminating between PD patients and controls was a 16‐item odor identification test. A combination of the 16‐item identification test and the detection threshold task had a significantly higher area under the curve than the 16‐item odor identification test alone. In conclusion, extended testing across, and not within, olfactory tasks increases diagnostic accuracy of olfactory testing in PD. A combination of an odor detection threshold task and a 16‐item odor identification test had the highest sensitivity and specificity in distinguishing between PD patients and controls. © 2008 Movement Disorder Society     

Circadian modulation of fos responses to odor of the red fox, a rodent predator, in the rat olfactory system

We have previously shown that neuronal responses to a biologically neutral odor, cedar wood oil, in the olfactory system are greater in the subjective night compared to subjective day. In the present study, we confirm these results and extend them to a biologically relevant odor, the urine of the red fox, a rodent predator. Fos induced by exposure of rats to fox urine or a neutral odor, mineral oil, was markedly enhanced during the subjective night compared to subjective day in the main olfactory bulb, primary olfactory cortex, and other structures related to olfaction. These results show that neuronal responses to an ethologically relevant odor follow a circadian rhythm similar to biologically neutral odors. Fos responses induced by fox urine were observed to be of greater magnitude than a neutral odor in brain areas involved in fear responses, suggesting that fox urine activates fear circuitry.     

Long-Term Outcome of Spinal Cord Stimulation for Chronic Pain Management

Study Design. This is a retrospective study on 102 patients subjected to implantation of a spinal cord stimulation system for nonmalignant chronic pain management. The study was conducted through an extensive questionnaire and telephone interviews by a neutral third party. All the patients were implanted with a complete spinal cord stimulation system without a preliminary trial with a temporarily implanted electrode. Diagnostic categories were neuropathic pain, failed back syndrome, spinal cord Injury pain, and miscellaneous. Average follow-up was 3.8 years (6 months to 8 years). Patients were divided in two groups: all the implanted patients in the survey (Group A) and the implanted patients who experienced some degree of pain relief with the stimulation (Group B). Group B (80 patients) closely matches previously published series where an initial temporary screening was performed. Results. Twenty-one percent of the patients never experienced any pain relief. Of the remaining 80, 75% were still using the stimulator. Fifty-one percent of the 80 patients were experiencing good to excellent results and 20% moderate results. There was no reduction over time in the amount of pain relief in patients who initially had at least 75% pain relief. Patients with initial pain relief between 50% and 74% observed a moderate reduction in their pain relief after two years. Patients who initially experienced less than 50% pain relief observed a dramatic reduction in their results in the long term follow-up. Psychological screening contributed to the success of the procedure. Conclusions. With proper medical and psychological screening and with demonstrated initial pain relief, spinal cord stimulation remains an effective modality in the long-term management of severe chronic pain.     

Descending pathways to the spinal cord: a comparative study of 22 mammals

In order to estimate the qualitative commonalities and range of variation among major descending spinal pathways relevant to mankind's ancestral lineage, the supraspinal cell groups originating fibers descending directly to the spinal cord were examined in 22 mammalian species. In a standardized retrograde tract-tracing procedure, flakes of raw HRP were applied directly to the freshly cut fibers of the spinal cord after it had been hemisected at the C1-C2 junction. After a 72-hour survival period, brain and spinal cord tissues were processed by conventional HRP-processing techniques. This procedure was performed on 94 individual animals. Of this total, 41 individual cases were eliminated by a rigorous culling procedure. The results are based on 53 individuals representing 15 species selected for their successive kinship with mankind and seven species in two other lineages selected for the convergence of their visual or sensorimotor systems with anthropoids. The 22 species represent 19 genera, 14 families, eight orders, and two subclasses of Mammalia. The results show that at least 27 supraspinal cell groups, each containing intensely labeled cells, can be readily identified in each of the species. Despite vast quantitative differences in cell number and cell size, this qualitative uniformity among the relatively large number of diverse taxa suggests that the same pathways were probably present in the extinct ancestors throughout mankind's mammalian lineage and are probably still present in extant viviparous mammals as well. If so, these pathways are as old in phylogenetic history as the last common ancestor of marsupial and placental mammals--dating from the late Jurassic to early Cretaceous, perhaps 145-120 million years ago. Further comparison of the results with similar experimental findings in members of other vertebrate classes supports the notion that several of these same pathways can be traced to even more remote ancestry, with some possibly as old as the entire vertebrate subphylum--dating from the early Devonian or before, perhaps 430 million years ago. Within mankind's ancestral lineage, from the appearance of vertebrates to the appearance of mammals, there seems to have been an irregular stepwise augmentation of the set of descending pathways until the full mammalian complement was finally attained with the appearance of the corticospinal tract.     

Traumatic brain injury assessed with olfactory event-related brain potentials.

Olfactory event-related potentials (OERPs) were evaluated to develop an objective, quantitative assessment of sensory and cognitive olfactory loss following traumatic brain injury (TBI). Subjects included 25 TBI patients and 25 age/gender-matched healthy controls. Following standard clinical evaluation of smell function, TBI patients were divided into three groups: 12 anosmics (loss of smell), 6 hyposmics (reduced smell), and 7 normosmics (normal smell). Cognitive ability was assessed using the Trail Making Test (A and B). OERPs were recorded monopolarly from midline electrode sites using an amyl acetate stimulus with a 60-second interstimulus interval; subjects estimated the magnitude of each odor stimulus. Anosmic TBI patients were also tested with OERPs using ammonia to ensure trigeminal nerve function. Amyl acetate OERPs demonstrated that the sensory N1 and P2 amplitudes and the cognitive P3 amplitudes were absent in the anosmic TBI patients and greatly reduced in the hyposmic and normosmic TBI patients compared to healthy controls. The trigeminal OERPs from the anosmic TBI patients were within normal limits, indicating that the primary olfactory deficits were objectively measured with OERPs. The relationship between the OERPs and neuropsychologic test performance supports the cognitive loss associated with TBI. The present study lends support to the utility of OERPs as an objective tool for measuring sensory and cognitive loss after traumatic brain injury.     

Spinal Cord Stimulation for Failed Back Surgery Syndrome

Objective. The purpose of this study is to evaluate the effectiveness of modern spinal cord stimulation (SCS) for the treatment of failed back surgery syndrome (FBSS). Materials and Methods. Thirty patients were treated with SCS between December 1992 and January 1998 for low back and radicular pain after multiple failed back surgeries. Permanent systems were implanted if trial stimulation led to > 50% pain reduction. Median long‐term follow‐up was 34 months (range, 6–66 months). Severity of pain was determined postoperatively by a disinterested third party. Results. Overall, 12 of the 16 patients (75%) who received permanent implants continued to report at least 50% relief of pain at follow‐up. All six patients who underwent placement of laminectomy‐styled electrode for SCS in the thoracic region had > 50% pain relief at long‐term follow‐up. Visual analog scores decreased an average of 3.2 (from 8.6 preoperatively to 5.4 postoperatively). Patients undergoing SCS placement via laminectomy in the thoracic region experienced an average decrease of 4.9 in VAS, whereas those who underwent percutaneous placement of thoracic leads had an average decrease of 2.5. Conclusions. SCS is an effective treatment for chronic low back and lower extremity pain which is refractory to conservative therapy and which is not amenable to corrective anatomic surgery. Though our patient population is small, our results imply that the laminectomy‐style electrodes in the thoracic region achieve better long‐term effectiveness than percutaneous leads.     

Characteristics of odorant elicited calcium changes in cultured human olfactory neurons

An important step in establishing and utilizing a cell culture system for the in vitro study of olfaction is assessing whether the cultured cells possess physiological properties similar to those of mature olfactory neurons. Various investigators have successfully established proliferating cell lines from olfactory tissue, but few have demonstrated the characteristics of odor sensitivity of these cells. We successfully established cultured cell lines from adult human olfactory tissue obtained using an olfactory biopsy procedure and measured their ability to respond to odor stimulation using calcium imaging techniques. A subset of the human olfactory cells in culture displayed a distinct morphology and specifically expressed immunocytochemical markers characteristic of mature human olfactory neurons such as OMP, G(olf), NCAM and NST. Under defined growth conditions, these cultured cells responded to odorant mixes that have been previously shown to elicit intracellular calcium changes in acutely-isolated human olfactory neurons. These odorant-elicited calcium responses displayed characteristics similar to those found in mature human olfactory neurons. First, cultured cells responded with either increases or decreases in intracellular calcium. Second, increases in calcium were abolished by removal of extracellular calcium. Third, inhibitors of the olfactory signal transduction cascades reversibly blocked these odorant-elicited intracellular calcium changes. Our results demonstrate that cultures of adult human olfactory cells established from olfactory biopsies retain some of the in vivo odorant response characteristics of acutely isolated cells from the adult olfactory epithelium. This work has important ramifications for investigation of olfactory function and dysfunction using biopsy procedures and in vitro assays of odor sensitivity.     

Understanding smell—The olfactory stimulus problem

The main problem with sensory processing is the difficulty in relating sensory input to physiological responses and perception. This is especially problematic at higher levels of processing, where complex cues elicit highly specific responses. In olfaction, this relationship is particularly obfuscated by the difficulty of characterizing stimulus statistics and perception. The core questions in olfaction are hence the so-called stimulus problem, which refers to the understanding of the stimulus, and the structure–activity and structure–odor relationships, which refer to the molecular basis of smell. It is widely accepted that the recognition of odorants by receptors is governed by the detection of physico-chemical properties and that the physical space is highly complex. Not surprisingly, ideas differ about how odor stimuli should be classified and about the very nature of information that the brain extracts from odors. Even though there are many measures for smell, there is none that accurately describes all aspects of it. Here, we summarize recent developments in the understanding of olfaction. We argue that an approach to olfactory function where information processing is emphasized could contribute to a high degree to our understanding of smell as a perceptual phenomenon emerging from neural computations. Further, we argue that combined analysis of the stimulus, biology, physiology, and behavior and perception can provide new insights into olfactory function. We hope that the reader can use this review as a competent guide and overview of research activities in olfactory physiology, psychophysics, computation, and psychology. We propose avenues for research, particularly in the systematic characterization of receptive fields and of perception.     

Treatment of Failed Back Surgery Syndrome Patients with Low Back and Leg Pain: A Pilot Study of a New Dual Lead Spinal Cord Stimulation System

Objective. Treatment of pain associated with failed back surgery syndrome was evaluated in a pilot clinical study of a new dual lead spinal cord stimulation (SCS) system. Methods. The following data was retrospectively sought from 20 non-randomized patients at 2 centers treated by the new SCS system, instead of an implantable drug pump: 1) prior back surgeries, 2) pain and paresthesia mapping, 3) VAS ratings, 4) medication use, 5) sleep patterns, 6) physical abilities, 7) hardware problems, and 8) willingness to repeat the procedure. Two-year follow-up was sought from all patients. Results. The new dual lead SCS system provided good low back and leg paresthesia coverage. Patients reported having less pain and using fewer analgesics and narcotics during follow-up, compared to their preimplant experience. These improvements were statistically significant. Patients also improved their sleep and physical abilities during follow-up. While external hardware problems occurred, 65% of dual lead SCS patients were willing to repeat the SCS implant procedure. Conclusions. Dual lead stimulation proved beneficial for patients with low back and leg pain associated with failed back surgery syndrome.     

In vivo neurochemical imaging of olfactory dysfunction in Parkinson’s disease

Olfactory dysfunction is common in Parkinson’s disease (PD) and has been attributed to early deposition of α-synuclein pathology in olfactory areas. The pathophysiology of olfactory dysfunction in PD, however, remains poorly understood. Changes in odor identification suggest in part impairment in odor memory, possibly due to hippocampal dysfunction. Olfactory dysfunction occurs also in Alzheimer’s disease (AD) and increases with severity of dementia. Cholinergic degeneration is not only a feature of AD but can also occur in PD, at least in a subset of patients with cognitive changes. We reported previously that impaired odor identification in early PD is more closely correlated with hippocampal dopaminergic than nigrostriatal dopaminergic denervation. Results of our multi-tracer PET studies show that odor identification deficits in PD are best predicted by cholinergic denervation and to a lesser extent by dopaminergic denervation. These results suggest that olfactory dysfunction in PD may have multiple components including hippocampal dysfunction secondary to cholinergic and dopaminergic denervations. Olfactory dysfunction in PD may be the most marked in subjects at risk of incipient dementia, and may reflect the transition of PD toward a stage with more heterogeneous multi-system neurodegenerations. Our preliminary imaging data do not support a significant contribution of amyloidopathy or serotoninergic denervation to abnormal olfactory functions in PD, at least in the absence of dementia. We outline how progressive changes in olfaction may be used as a biomarker of cholinergic denervation and cognitive decline in PD patients. We will discuss also the utility of olfactory testing as an early screening test for neurodegeneration.     

The Effects of Temporary Spinal Cord Stimulation (or Spinal Nerve Root Stimulation) on the Management of Early Postherpetic Neuralgia from One to Six Months of Its Onset

Objective: We examined the efficacy of temporary spinal cord stimulation involving the insertion of only a needle and quadripolar lead into the epidural space and applied using an extracorporeal stimulation generator for a few weeks of early postherpetic neuralgia from one to six months of its onset. Materials and Methods: Temporary spinal cord stimulation was applied in 33 patients with postherpetic neuralgia and in whom epidural block was effective. Temporary spinal cord stimulation was applied over seven days, and analgesic effects was evaluated based on visual analog scale (VAS) values before and after one, three, and six months following treatment. An analgesic effect was defined as a decrease of over 50% in the VAS value compared with before treatment. Results: VAS values decreased significantly from 68.1 mm (standard deviation [SD]± 15.2) before treatment to 37.5 mm (SD ± 20.4) after one month, to 38.0 mm (SD ± 18.7) after three months, and to 35.0 mm (SD ± 21.3) after six months. In 21/33 (63.6%) cases, an analgesic effect, defined as a decrease in the VAS value of greater than 50%, was observed one month after treatment, in 20/33 (60.6%) cases such an effect was observed three months after treatment, and in 21/33 (63.6%) cases the effect was still observed six months after treatment. Conclusions: Temporary spinal cord stimulation is an effective analgesic method for early postherpetic neuralgia from one to six months of its onset.