Improvement in smell and taste dysfunction after repetitive transcranial magnetic stimulation

Article Outline

• Abstract
• 1. Introduction
• 2. Methods
  • 2.1. Study design
  • 2.2. Patients
  • 2.3. Measurement techniques
  • 2.4. Treatment protocol
  • 2.5. Outcome measures
• 3. Results
  • 3.1. Pre–rTMS I (before treatment)
    • 3.1.1. Sensory distortions
    • 3.1.2. Taste
    • 3.1.3. Smell
  • 3.2. rTMS I (first trial)
    • 3.2.1. Sham procedure (0.3–0.5 T)
    • 3.2.2. Sham procedure (0.08–0.12 T)
  • 3.3. rTMS trial (0.8–1.1 T)
    • 3.3.1. Sensory distortions
    • 3.3.2. Taste
    • 3.3.3. Smell
  • 3.4. Post–rTMS I
  • 3.5. rTMS II
    • 3.5.1. Sham procedure (0.3–0.5 T)
    • 3.5.2. Sham procedure (0.08–0.12 T)
  • 3.6. rTMS trial (0.8–1.1 T)
    • 3.6.1. Sensory distortions
    • 3.6.2. Taste
    • 3.6.3. Smell
  • 3.7. Post–rTMS II
  • 3.8. rTMS III
• 4. Discussion
• References
• Copyright

Abstract 

Background

Olfactory and gustatory distortions in the absence of odors or tastants (phantosmia and phantageusia, respectively) with accompanying loss of smell and taste acuity are relatively common symptoms that can occur without other otolaryngologic symptoms. Although treatment of these symptoms has been elusive, repetitive transcranial magnetic stimulation (rTMS) has been suggested as an effective corrective therapy.

Objective

The objective of the study was to assess the efficacy of rTMS treatment in patients with phantosmia and phantageusia.

Methods

Seventeen patients with symptoms of persistent phantosmia and phantageusia with accompanying loss of smell and taste acuity were studied. Before and after treatment, patients were monitored by subjective responses and with psychophysical tests of smell function (olfactometry) and taste function (gustometry). Each patient was treated with rTMS that consisted of 2 sham procedures followed by a real rTMS procedure.

Results

After sham rTMS, no change in measurements of distortions or acuity occurred in any patient; after initial real rTMS, 2 patients received no benefit; but in the other 15, distortions decreased and acuity increased. Two of these 15 exhibited total inhibition of distortions and return of normal sensory acuity that persisted for over 5 years of follow-up. In the other 13, inhibition of distortions and improvement in sensory acuity gradually decreased; but repeated rTMS again inhibited their distortions and improved their acuity. Eighty-eight percent of patients responded to this therapeutic method, although repeated rTMS was necessary to induce these positive changes.

Interpretation

These results suggest that rTMS is a potential future therapeutic option to treat patients with the relatively common problems of persistent phantosmia and phantageusia with accompanying loss of taste and smell acuity. Additional systematic studies are necessary to confirm these results.

Back to Article Outline

1. Introduction 

We first reported smell and taste dysfunction in 1971 [1] as loss of smell and taste acuity [1], [2], [3], [4] and presence of olfactory and gustatory distortions [1], [2], [3], [4], [5], [6]. Acuity loss comprised multiple degrees from the rare occurrence of total absence of smell or taste (anosmia or ageusia, respectively) to the more common relative loss of smell or taste acuity (hyposmia or hypogeusia, respectively) [1], [2], [3], [4]. Smell and taste distortions commonly followed acuity loss [1], [2], [3], [4], [5], [6]. Distortions were of 2 major types. One type related to obnoxious odors and tastes in the absence of environmental odors or food and drink, labeled phantosmia or phantageusia, respectively [1], [2], [3], [4], [5], [6]; phantosmias can occur in either one [5] or in both nares [6], whereas phantageusias are usually orally global. The other related to obnoxious smells or tastes generated from environmental odors or common foods and drinks, labeled aliosmia or aliageusia, respectively [1], [2], [3], [4], [5], [6].

Over the 38 years since our initial report [1] with its accompanying editorial [7], we learned that these symptoms affected many millions of patients in the United States [3], [4]. We [1], [2], [3], [4], [5], [6], [7] and many others [8], [9], [10], [11], [12], [13] studied these patients and developed a greater understanding of their symptoms. For clinical diagnosis, we [1], [2], [3], [4], [5], [6], [7], [13] and others [8], [9], [10], [11], [12], [14], [15], [16], [17] developed complex psychophysical (olfactometry for smell, gustometry for taste) and functional neuroradiologic paradigms. For clinical etiology, we developed biochemical analyses of blood, urine, saliva, and nasal mucus that allowed classification of patients into groups based upon specific biochemical parameters [18], [19], [20], [21]. For treatment, we initiated pharmacologic protocols to increase concentrations of putative growth factors responsible for taste bud and olfactory epithelial stem cell differentiation and maturation [22], [23]. However, definitive treatment for patients with relatively common symptoms of phantosmia and phantageusia remains elusive.

To understand more about phantosmia and phantageusia, we used functional magnetic resonance imaging of brain with olfactory signals [5], [6], [13] and magnetic resonance brain spectroscopy [24] to study neurotransmitter changes with respect to these symptoms. These studies revealed that central nervous system (CNS) γ-aminobutyric acid (GABA) levels among patients with phantosmia and phantageusia were decreased in specific CNS regions [24] and that treatment with GABAergic drugs increased regional CNS GABA and corrected these sensory distortions [24], [25]. These results suggested that CNS GABA played a prominent role in modulating these sensory distortions [24], [25]. Because transcranial magnetic stimulation (TMS) has been reported to influence GABA [26], [27] as well as other neurotransmitters including dopamine [28], [29], biogenic amines [30], serotonin [31], and 5–hydroxyindoleacetic acid [32], we wondered whether this treatment could be effective in treating these sensory distortions because repetitive TMS (rTMS) has been reported to modify CNS excitability [33], [34], to enhance sensory function [35], to alter cognition [36], and to alter concentrations of several neurotransmitters, as noted above. Repetitive TMS has also been reported to be useful in treating several neurologic conditions including rehabilitation after ischemic stroke [37], decreasing some symptoms of Parkinson disease (PD) [38], and inhibiting tinnitus [39]. In a prior pilot study, we demonstrated that rTMS decreased phantosmia and phantageusia through a putative role in modulating CNS plasticity [25], [27].

To test the hypothesis that rTMS might alleviate phantosmia and phantageusia, we initiated a clinical study to evaluate effects of rTMS in a more systematic manner in a small group of carefully studied patients with these symptoms.

Back to Article Outline

2. Methods 

2.1. Study design 

This was a prospective sham-controlled, fixed-sequence, open clinical trial conducted between June 1999 and June 2005. Changes in the presence of sensory distortions and loss of sensory acuity before and after 3 trials of rTMS were measured. This study was approved by the Institutional Review Board of the George Washington University Medical Center.

2.2. Patients 

Seventeen right-handed white patients—5 men aged 40 to 74 years (58 ± 7 years, mean ± SEM) and 12 women aged 30 to 76 years (51 ± 5 years)—were studied at The Taste and Smell Clinic (The Clinic) and at the Department of Neurology at the George Washington University Medical Center, both in Washington, DC. Each patient had mild to severe persistent birhinal phantosmia and/or global oral phantageusia that was profound and interfered with normal life pursuits. Each patient also had mild to severe persistent hyposmia and hypogeusia. Before this study, sensory distortions persisted for 3 months to 30 years (3.7 ± 2 years); acuity loss persisted for 6 months to 30 years (4.1 ± 2 years). Etiologies that initiated these symptoms were head injury [40] (4 patients), post influenza-like infection (PIHH) [41] (7 patients), idiopathic causes [3] (4 patients), and drug reactions [42] (2 patients). Patients were each of 17 consecutive patients who presented to The Clinic with these symptoms and were treated with rTMS.

None had either clinical otolaryngologic or neurologic symptoms other than loss of sensory acuity and presence of sensory distortions. None had any psychiatric symptom other than some depression associated with persistence of these sensory impairments. Results of physical examination of each patient including examination of the head and neck and general neurologic examination were within normal limits. Results of both anatomical brain magnetic resonance imaging and electroencephalograms were within normal limits in each patient.

Prior treatment with multiple agents including antiepileptics, anxiolytics, antidepressants, trace metals, vitamins, and a variety of alternative treatment strategies including herbal remedies, acupuncture, chiropractic techniques, or hypnosis did not influence any of their symptoms.

2.3. Measurement techniques 

Olfactory and gustatory distortions were graded daily by the patient with respect to intensity, duration, and frequency using a written record on a 0 to 100 scale for 3 days to 4 weeks before rTMS; 0 reflected total absence of sensory distortions, and 100 reflected the digitized composite of the most intense distortions experienced over the entire day. Records were reviewed before the study by one of the investigators (RIH) to ensure understanding of symptom grading.

Taste acuity and smell acuity were each determined by a standard 3-stimuli forced-choice staircase technique [3], [4]. Detection (DT) and recognition (RT) thresholds and magnitude estimation (ME) for 4 tastants (NaCl [salt], sucrose [sweet], HCl [sour], and urea [bitter]) (for gustometry) and 4 odorants (pyridine [dead fish], nitrobenzene [bitter almond], thiophene [old motor oil], and amyl acetate [banana oil]) (for olfactometry) were obtained, and results were compared with reference values previously established for normal subjects [3], [43]. All DTs and RTs for tastants and odorants, respectively, were converted into bottle units (BU) [3], [44]. ME was determined by methods previously described, calculated in percentage for each stimulus, and compared with previously established standards [3], [44]. Reliability of these techniques was confirmed by studies performed in a previously published controlled double-blind clinical trial [44].

The entire battery of sensory measurements was obtained at the initial patient visit to The Clinic and repeated immediately before and after each rTMS trial. This battery was also repeated at variable intervals after each rTMS trial. Each test battery and rTMS trial were performed independent of knowledge of any prior result.

2.4. Treatment protocol 

Repetitive TMS was performed with a Cadwell (Kennewick, WA) magnetoelectric stimulator MES-10 monitored by a TECA TD20 (Pleasantville, NY) wave form generator. Stimulation was applied by use of a single circular 5-cm (internal diameter) coil.

Three consecutive stimulation procedures were used at each rTMS trial. The first 2 were sham procedures; the third was the real trial. Each procedure consisted of the patient viewing the stimulating instrument and, with each activation and disappearance of the signal, visualizing the on and off appearance of a green light and hearing an on and off sound of the activity stimulus click.

The first procedure was a sham procedure consisting of applying 20 stimuli at intervals of 1 to 5 seconds at 25% to 35 % maximal output (25–35% of 1.5 T or ∼0.3–0.5 T [because stimulus delivery was nonlinear]) sequentially (a) to the anterior right shoulder (at the lateral acromial process of the clavicle [near Erb point]), then (b) to the anterior left shoulder (near Erb point), and then (c) to the back of the midneck region (at the level of C5–8 at 30–40% maximal output or ∼0.4–0.8 T); mild to moderate muscle group flexion of arm and hand muscles (shoulder stimulation) and neck, strap, and facial muscles (neck stimulation), respectively, followed stimulation at each respective site and was visually monitored.

The second procedure was another sham procedure consisting of applying 20 stimuli at intervals of 1 to 5 seconds at 10% to 15% maximal output (10–15% of 1.5 T or ∼0.08–0.15 T, a subthreshold stimulus) sequentially to 4 skull regions in a fixed sequence (left temporoparietal, occipital, right frontoparietal, frontal). No subjective or peripheral muscle response occurred in response to this stimulation.

The third procedure was the real trial consisting of applying 20 stimuli at intervals of 1 to 5 seconds at 40% to 55% maximal output (∼0.8–1.1 T) sequentially to each skull location as in the second sham procedure noted above. Right/left thenar and/or phalangeal flexion after left/right temporoparietal stimulation, respectively, occurred and was monitored by visual observation. Mild facial muscle flexion usually occurred after occipital stimulation, and bilateral eye blinking usually occurred after frontal stimulation.

After each sham procedure and real rTMS trial, changes in intensity and character of phantosmia and/or phantageusia and/or olfactory response to a single odor were recorded. If any change in sensory distortion or in olfactory acuity occurred, stimulation at that location at that same intensity was repeated 2 to 6 times until no further change occurred.

2.5. Outcome measures 

After completion of studies in all patients, mean ± SEM of changes in sensory distortion intensity and of taste and smell acuity (DT, RT, ME) were calculated; and significance of differences was determined by Student t tests. Differences of P < .05 were considered significant. Differences were also calculated using paired t tests with significance determined by Student t test (results of these tests are not shown). Differences of P < .05 were considered significant.

Back to Article Outline

3. Results 

3.1. Pre–rTMS I (before treatment) 

Mean phantageusia intensity was 82% ± 7%; mean phantosmia intensity was 72% ± 14% (Table 1). There were no sex differences in either phantageusia or phantosmia intensity (Table 2).

Table 1. Changes in phantageusia and phantosmia in 17 patients with hyposmia, hypogeusia, phantosmia, and/or phantageusia pre– and post–rTMS I

Number of patients in parentheses.

^⁎ Mean ± SEM (in percentage, of most intense distortions experienced throughout waking state [39]).

Compared with pre–rTMS 1:

^†P < .001.

^‡P < .005.

^§P < .02.

^║P < .025.

Table 2. Changes in taste and smell acuity in 17 patients with hypogeusia, hyposmia, phantosmia, and/or phantageusia pre– and post–rTMS I compared with normal responses

Detection threshold in BU, RT in BU, and ME in percentage. Normal refers to 150 normal volunteers [3], [43].

^⁎ Mean ± SEM (in BU [44]).

^† Mean± SEM (in percentage [44]).

Compared with normal:

^‡P < .001.

^§P < .005.

^║P < .01.

^¶P < .02.

^#P < .025.

**P < .05.

Compared with pre–rTMS I:

^‡1P < .001.

^§1P < .005.

^║1P < .01.

^¶1P < .02.

^#1P < .025.

**¹P < .05.

Mean DTs and RTs for all tastants except DT for HCl were significantly higher than normal (ie, taste acuity was decreased) (Table 2). Mean MEs for all tastants were significantly less than normal (ie, taste intensity was decreased) (Table 2).

Mean DTs and RTs for all odorants except DTs for pyridine, thiophene, and amyl acetate were significantly higher than normal (ie, smell acuity was decreased) (Table 2). Mean MEs for all odorants were significantly less than normal (ie, smell intensity was decreased) (Table 2).

3.2. rTMS I (first trial) 

No subjective or objective changes occurred in either character or intensity of sensory distortions or in taste and/or smell acuity.

No subjective or objective changes occurred in either character or intensity of sensory distortions or in taste and/or smell acuity.

3.3. rTMS trial (0.8–1.1 T) 

Mean phantageusia and phantosmia intensity decreased significantly (Table 1). However, no changes occurred in 2 patients (labeled nonresponders), whereas significant improvement occurred in 15 (labeled responders). In each man, phantosmia disappeared.

Mean DTs and RTs for all tastants decreased (ie, taste acuity increased), but they were significantly decreased only for DT and RT for NaCl and RT for urea (Table 2). The DT and RT for other tastants decreased 22% to 58% (Table 1). Mean DT and RT for NaCl, sucrose, and HCl decreased to normal levels; as did DT for urea. Only mean RT for urea did not decrease to normal, although it was significantly lower than that before treatment (Table 2). Mean MEs for all tastants increased (ie, taste intensity increased), but they increased significantly only for HCl. Mean ME for other tastants increased 26% to 43% (Table 1). Mean MEs for all tastants returned to normal levels, although all responses were decreased (less sensitive) compared with normal subjects (Table 2).

Mean DTs and RTs for all odorants except RT for thiophene decreased significantly (ie, smell acuity increased) (Table 2). Mean DT and RT for pyridine, nitrobenzene, and thiophene and mean DT for amyl acetate decreased to or less than normal levels (Table 2). Only mean RT for amyl acetate did not return to normal, although it was significantly less than values obtained before rTMS I (ie, acuity increased). Mean MEs for all odorants increased (ie, smell intensity increased), but the increase was significant only for thiophene and amyl acetate. Mean ME increased 48% for pyridine and 50% for nitrobenzene. Mean ME for all odorants increased to normal levels, although they were slightly less than the normal mean for both thiophene and amyl acetate.

Symptom improvement occurred (vs) in all responders only when the field was applied at 1 of the 4 skull locations. In 7 patients, improvement occurred only after left frontoparietal stimulation; in 4 (27%), only after right frontoparietal stimulation; in 3 (20%), only after frontal stimulation; and in 1 (7%), only after occipital stimulation. There was no improvement in nonresponders no matter where the field was applied.

3.4. Post–rTMS I 

In 2 of the responders, sensory distortions disappeared, and taste and smell acuity returned to normal; and these measurements persisted for as long as measurements were obtained (5 years). However, 4 to 32 weeks after rTMS I, subjective reports and repeated measurements of sensory distortion intensity and testing of taste and smell acuity indicated that sensory dysfunction gradually returned in 13 of the 15 responders or 76% of the 17 patients (Table 3, Table 4). A second trial of rTMS (rTMS II) was instituted.

Table 3. Changes in phantageusia and phantosmia in 13 patients with hyposmia, hypogeusia, phantosmia, and/or phantageusia pre– and post–rTMS II

Number of patients in parentheses.

^⁎Mean ± SEM (in percentage, of most intense distortion experienced throughout waking state [39]).

Compared with pre– and post–rTMS I and pre–TMS II:

^†P < .001.

Compared with pre–rTMS II and post–rTMS I:

^†1P < .001.

Compared with pre–rTMS I:

^†2P < .001.

^‡2P < .005.

Compared with pre–rTMS II:

^§3P < .02.

^║3P < .025.

Table 4. Changes in taste and smell acuity in 13 patients with hyposmia, hypogeusia, phantosmia, and/or phantageusia pre– and post–rTMS II and compared with normal responses

Number of patients in parentheses.

^⁎Mean ± SEM (in BU [44]).

^†Mean ± SEM (in percentage [44]).

Compared with normal:

^‡P < .001.

^§P < .005.

^║P < .01.

^¶P < .02.

^#P < .025.

**P < .05.

Compared with pre–rTMS II:

^‡1P < .001.

^§1P < 05.

^║1P < .01.

^¶1P < .02.

^#1P < .025.

**¹P < .05.

Compared with post–rTMS I:

^‡2P < .001.

^§2P < .005.

^║2P < .01.

^¶2P < .02.

^#2P < .025.

**²P < .05.

3.5. rTMS II 

No subjective or objective changes occurred in character or intensity of sensory distortions or in either taste and/or smell acuity.

No subjective or objective changes occurred in character or intensity of sensory distortions or in either taste and/or smell acuity.

3.6. rTMS trial (0.8–1.1 T) 

Phantageusia and phantosmia both decreased significantly (Table 3), similar to results after rTMS I (Table 1). Phantosmia completely disappeared (all men and women), not just in men as after rTMS I (Table 1). Phantageusia disappeared in 10 patients, and improved by 50% in one and only slightly in two. Mean phantageusia and phantosmia intensity decreased to levels less than those measured later post-rTMS I (cf, Table 1, Table 3).

Mean DTs and RTs for all tastants decreased (ie, taste acuity increased), but decreases were significant only for DT for NaCl and urea and RT for HCl and urea. Other DTs decreased 16% to 33%, and RTs decreased 31% to 35% (Table 4). Compared with normal, responses for all DTs and RTs were not significantly different, with responses lower than normal (more sensitive) for DTs for NaCl, sucrose, and urea but responses higher than normal (less sensitive) for all RTs.

Mean MEs for all tastants increased (ie, taste intensity increased), with increases ranging from 30% to 62% (Table 4). The MEs for all tastants were within the normal range, with responses for sucrose and HCl slightly higher than the normal mean (increased intensity), whereas responses for urea were slightly less than the normal mean (decreased intensity).

Mean DTs and RTs for all odorants decreased (ie, smell acuity increased) and were significantly decreased for DT for thiophene and amyl acetate and RT for nitrobenzene, thiophene, and amyl acetate (Table 4). All DTs and RTs were in the normal range (Table 3).

3.7. Post–rTMS II 

Although improvement in sensory dysfunction was initially obtained in all of these 13 patients within 1 hour of stimulation at the same brain locus at which improvement occurred after rTMS I, these changes persisted only in 7 or 54% (1 with head injury, 4 with PIHH, 2 with idiopathic hyposmia) for as long as measurements were made (40 months after rTMS II). In the remaining 6 or 46% (1 with head injury, 1 with PIHH, the 2 with idiopathic causes, the 2 with drug reactions), symptoms of sensory impairment gradually returned after 3 to 6 months; but sensory distortions were less intense and acuity was less impaired than before rTMS II. Therefore, a third trial of rTMS was instituted.

3.8. rTMS III 

These 6 patients were again treated with rTMS as in rTMS I and II. Both sham procedures were again ineffective in changing sensory dysfunction, but real rTMS was again effective in decreasing sensory distortions and in improving sensory acuity within 1 hour of stimulation again only at the same brain locus that initiated improvement after prior stimulation (data not shown). Reports of disappearance of all sensory distortions and of normal sensory acuity in these patients persisted for as long as they were followed (6–42 months).

Back to Article Outline

4. Discussion 

Results indicate that rTMS was efficacious in inhibiting phantosmia and phantageusia and in improving taste and/or smell acuity, although one or more treatment procedures were required to obtain clinically useful results.

Improvement occurred most often after rTMS was applied at the left frontoparietal brain region, although spread of magnetic activity from one stimulation site to other portions of the brain is known to occur. With recurrent symptomatology, repeated rTMS was effective in improving symptoms but only after application at the same site at which initial improvement occurred, mainly the left frontoparietal region, a locus contralateral to patient handedness.

This result is consistent with previous studies indicating enhanced sensory processing after rTMS at one brain locus, mainly left prefrontal cortex [45]. Improvement after initial stimulation at one brain locus and reinitiated with repeated stimulation at this same locus is consistent with results noted by Ziemann et al [46] in prior rTMS studies. These results are also consistent with prior results that rTMS produced persistent effects after repeated stimulation and after stimulation ended [47], [48]. Prior reports also noted that stimulation of motor cortex of one hemisphere inhibited activity in the homologous area of the contralateral cortex [49].

Sham rTMS has been reported to induce positive behavioral effects and to induce significant dopamine release in bilateral striatum in patients with PD consistent with an expectation of benefit [50]. In our study, sham stimulation had no effect on sensory dysfunction. Although placebo effects play important roles in any open trial and sham rTMS has induced changes in brain dopamine concentrations [51], our data indicate that sham stimulation did not alter sensory dysfunction. This lack of placebo effect may be recognized from our results, in which (a) changes after rTMS persisted as long as 6 to 60 months, whereas placebo effects are usually transient; (b) improvement occurred after stimulation at only 1 of 4 CNS regions over 3 consecutive trials, with stimulation in other regions not initiating any changes; (c) positive effects of rTMS occurred in our study, whereas all patients were refractory to all prior treatments (including a variety of putative therapeutic agents and processes); and (d) the repeated recurring improvement and regression of symptoms after repeated rTMS persisted for more extended periods after each treatment, suggesting a specific effect of rTMS.

The mechanism(s) by which rTMS decreased sensory distortions of taste and smell may be related to changes in brain plasticity [52], [53]. With improvement in sensory function, CNS reorganization may occur such that prior CNS dysplasticity may be inhibited and more normal function may return. It is well known that significant loss of sensory function is associated with subsequent generation of brain dysplasticity [54] with hallucinatory activity (eg, phantom limb syndrome [54]), consistent with CNS reorganization with what has been considered deafferentation hypersensitivity [54]. Repetitive TMS has been considered to enhance neural plasticity [52], [53], [54].

The mechanism(s) by which rTMS increased acuity of taste and smell is unclear. Sandyk [55] reported transient improvement in olfactory acuity in 2 patients with PD treated with alternating current pulsed electromagnetic fields and related these changes to increased brain dopamine. Patients with PD commonly exhibit decreased smell acuity [56] and exhibit impaired brain dopamine metabolism [57]. One of 3 patients with PD improved olfactory acuity with l-dopa [58]; and diminished intensity, duration, and intensity of phantosmia occurred with l-dopa in an anecdotal case report of one PD patient [59]. Increased brain dopamine reported after rTMS [50], [58] could improve olfactory function because this neurotransmitter plays a role in olfaction, as noted earlier. However, changes in other neurotransmitters after rTMS including catacholamines [30], serotonin [31], [60], and GABA [28], [29] and interactions among these moieties [30], [61] could also improve taste and smell function. γ-aminobutyric acid and GABA receptor activity has been measured in the olfactory bulb [61], [62]; and GABA activity in the olfactory bulb has been reported to be modulated by dopamine receptors [63], to interact with adenylyl cyclase activity [64], and thereby to play a role in odor DT, discrimination, and olfactory learning [65]. Disruption of this GABA network had negative effects on olfactory discrimination [66].

This study suggests that patients with persistent phantosmia and phantageusia related to several etiologies are candidates for this simple, novel mode of therapy and should provide a method for otolaryngologists to treat these relatively common maladies. Further systematic studies are necessary to extend and confirm these results.

Back to Article Outline

References 

1. Henkin RI, Schechter PJ, Hoye RC, et al. Idiopathic hypogeusia with dysgeusia, hyposmia and dysosmia: a new syndrome. J Am Med Assoc. 1971;217:434–440
   • View In Article
2. Henkin RI. Disorders of taste and smell. JAMA. 1971;218:1946
   • View In Article
   • MEDLINE
3. Henkin RI. Evaluation and treatment of human olfactory dysfunction. In:  English GM editors. Otolaryngology. vol 2:Philadelphia (PA): Lippincott; 1993;p. 1–86
   • View In Article
4. Henkin RI. Taste and smell disorders, human. In:  Adelman G,  Smith BH editor. Encyclopedia of neuroscience. 3rd ed.. Boston (MA): Birkhauser; 2004;
   • View In Article
5. Levy LM, Henkin RI. Physiologically initiated and inhibited phantosmia: cyclic, unirhinal, episodic, recurrent phantosmia revealed by brain fMRI. J Comput Assist Tomogr. 2000;24:501–520
   • View In Article
   • MEDLINE
   • CrossRef
6. Henkin RI, Levy LM, Lin CS. Taste and smell phantoms revealed by functional magnetic resonance imaging (fMRI). J Comput Assist Tomogr. 2000;24:106–123
   • View In Article
   • MEDLINE
   • CrossRef
7. Idiopathic hypogeusia, a new disease. JAMA. 1971;217:471–472
   • View In Article
   • MEDLINE
8. Atkin-Thor E, Goddard BW, O'Nion J, et al. Hypogeusia and zinc depletion in chronic dialysis patients. Am J Clin Nutr. 1978;31:1948–1951
   • View In Article
   • MEDLINE
9. Tomita H, Ishii T, Mikoshiba H, et al. Combined disorders of taste and smell. Otologia. 1981;27(Suppl 1):259–264
   • View In Article
10. Scott AE. Clinical characteristics of taste and smell disorders. Ear Nose Throat J. 1989;68:297–315
    • View In Article
    • MEDLINE
11. Doty RL. Olfactory dysfunction in neurodegenerative disorders. In:  Getchell TV,  Doty RL,  Bartoshuk LM, et al. editor. Smell and taste in health and disease. New York (NY): Raven Press; 1991;p. 735–751
    • View In Article
12. Mott AE, Leopold DA. Disorders in taste and smell. Med Clin North Am. 1991;75:1321–1352
    • View In Article
    • MEDLINE
13. Levy LM, Henkin RI, Hutter A, et al. Functional MRI of human olfaction. J Comput Assist Tomogr. 1997;21:849–856
    • View In Article
    • MEDLINE
    • CrossRef
14. In:  Meiselman HL,  Rivlin RS editor. Human taste and smell: measurements and uses. New York (NY): MacMillan; 1986;
    • View In Article
15. Cain WS, Gent JS, Catalanotto FA, et al. Clinical evaluation of olfaction. Am J Otolaryngol. 1983;4:252–256
    • View In Article
    • MEDLINE
    • CrossRef
16. Poellinger A, Thomas R, Liu P, et al. Activation and habituation in olfaction-an fMRI study. Neuroimage. 2001;13:547–560
    • View In Article
    • MEDLINE
    • CrossRef
17. Youssem DM, Maldigian JA, Siddiqi F, et al. Gender effects on odor-stimulation functional magnetic imaging. Brain Res. 1999;868:480–487
    • View In Article
18. Henkin RI, Velicu I, Papathanassiu A. cAMP and cGMP in human parotid saliva: relationships to taste and smell dysfunction, gender and age. Am J Med Sci. 2007;334:431–440
    • View In Article
    • CrossRef
19. Henkin RI, Velicu I. Decreased parotid salivary cyclic nucleotides related to smell loss severity in patients with taste and smell dysfunction. Metabolism. 2009;58:1717–1723
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (133 KB)
    • CrossRef
20. Henkin RI, Velicu I. cAMP and cGMP in nasal mucus: relationships to taste and smell dysfunction, gender and age. Clin Invest Med. 2008;31:E71–E77
    • View In Article
21. Henkin RI, Velicu I. cAMP and cGMP in nasal mucus related to severity of smell loss in patients with smell dysfunction. Clin Invest Med. 2008;31:E78–E84
    • View In Article
22. Henkin RI, Martin BM, Agarwal RP. Efficacy of exogenous zinc in treatment of patients with carbonic anhydrase VI deficiency. Am J Med Sci. 1999;318:392–404
    • View In Article
    • MEDLINE
    • CrossRef
23. Henkin RI, Velicu I, Schmidt L. An open label controlled trial of theophylline for treatment of patients with hyposmia. Am J Med Sci. 2009;337:396–406
    • View In Article
    • CrossRef
24. Levy LM, Henkin RI. Brain GABA levels are decreased in patients with phantageusia and phantosmia demonstrated by magnetic resonance spectroscopy. J Comput Assist Tomogr. 2004;28:721–727
    • View In Article
    • MEDLINE
    • CrossRef
25. Henkin RI, Potolicchio SJ, Levy LM. Rapid changes in taste and smell function following transcranial magnetic stimulation (TCMS) in humans: relationships to CNS plasticity. FASEB J. 2002;16:A875
    • View In Article
26. Werhahn KJ, Kunesch E, Noachtar S, et al. Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans. J Physiol. 1999;517:591–597
    • View In Article
    • CrossRef
27. Cohen LG, Ziemann U, Chen R, et al. Studies of neuroplasticity with transcranial magnetic stimulation. J Clin Neurophysiol. 1998;15:305–324
    • View In Article
    • MEDLINE
    • CrossRef
28. Zangen A, Hyodo K. Transcranial magnetic stimulation induces increases in extracellular levels of dopamine and glutamate in the nucleus accumbens. Neuroreport. 2002;13:2401–2405
    • View In Article
    • MEDLINE
    • CrossRef
29. Funamizu H, Ogiue-Ikeda M, Mukai H, et al. Acute repetitive transcranial magnetic stimulation reactive-dopaminergic system in lesion rats. Neurosci Lett. 2005;383:77–81
    • View In Article
    • MEDLINE
    • CrossRef
30. Keck ME, Sillaber I, Ebner K, et al. Acute transcranial magnetic stimulation of frontal brain regions selectively modulates the release of vasopressin, biogenic amines and amino acids in the rat brain. Eur J Neurosci. 2000;12:3713–3720
    • View In Article
    • CrossRef
31. Kanno M, Matsumoto M, Togashi H, et al. Effects of acute repetitive transcranial magnetic stimulation on extracellular serotonin concentration in the rat prefrontal cortex. J Pharmacol Sci. 2003;93:451–457
    • View In Article
    • MEDLINE
    • CrossRef
32. Gur E, Lerner B, van de Kar LD, et al. Chronic rTMS induces subsensitivity of post-synaptic 5-HTIA receptors in rat hypothalamus. Int J Neuropsychopharmacol. 2004;7:335–340
    • View In Article
    • MEDLINE
    • CrossRef
33. Ziemann U, Tergau F, Bruns D, et al. Changes in human motor cortex excitability induced by dopaminergic and anti-dopaminergic drugs. Electroencephalogr. Clin Neurophysiol/Electromyogr Motor Control. 1997;105:430–437
    • View In Article
34. Hallett M. Transcranial magnetic stimulation and the human brain. Nature. 2000;406:147–150
    • View In Article
    • MEDLINE
    • CrossRef
35. Merabet LB, Theoret H, Pascual-Leone A. Transcranial magnetic stimulation as an investigative tool in the study of visual function. Optom Vis Sci. 2003;80:356–368
    • View In Article
    • MEDLINE
    • CrossRef
36. Jahanshahi M, Rothwell J. Transcranial magnetic stimulation of cognition: an emerging field. Exp Brain Res. 2000;131:1–9
    • View In Article
    • MEDLINE
    • CrossRef
37. Khedr EM, Ahmed MA, Fathy N, et al. Therapeutic trial of repetitive transcranial magnetic stimulation after acute ischemic stroke. Neurology. 2005;65:466–468
    • View In Article
    • CrossRef
38. Mally J, Stone TW. Improvement in parkinsonian symptoms after repetitive transcranial magnetic stimulation. J Neurol Sci. 1999;162:179–184
    • View In Article
    • CrossRef
39. De Ridder D, Verstraeten E, Van der Kelen K, et al. Transcranial magnetic stimulation for tinnitus: influence of tinnitus duration on stimulation parameter choice and maximal tinnitus suppression. Otol Neurotol. 2005;26:616–619
    • View In Article
    • MEDLINE
    • CrossRef
40. Schechter PJ, Henkin RI. Abnormalities of taste and smell following head trauma. J Neurol Neurosurg Psychiatr. 1974;37:802–810
    • View In Article
41. Henkin RI, Larson AL, Powell RD. Hypogeusia, dysgeusia. hyposmia and dysosmia following influenza-like infection. Ann Otol Rhin Laryngol. 1975;84:672–682
    • View In Article
42. Henkin RI. Drug induced taste and smell disorders: incidence, mechanisms and management related primarily to treatment of sensory receptor dysfunction. Drug Safety. 1994;11:310–377
    • View In Article
43. Henkin RI. Newer aspects of copper and zinc metabolism. In:  Mertz W,  Hopkins L editor. New trace metals and nutrition. New York (NY): Marcel Dekker; 1971;p. 255–311
    • View In Article
44. Henkin RI, Schecter PJ, Friedewald WT, et al. A double blind study of the effects of zinc sulfate on taste and smell dysfunction. Am J Med Sci. 1976;272:285–299
    • View In Article
    • MEDLINE
    • CrossRef
45. Boroojerdi B, Phipps M, Kopylev L, et al. Enhancing analogic reasoning with rTCMS over the left prefrontal cortex. Neurology. 2001;56:526–528
    • View In Article
    • MEDLINE
46. Ziemann U, Lonnecker S, Steinhoff BJ, et al. Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol. 1996;40:367–378
    • View In Article
    • MEDLINE
    • CrossRef
47. Quartarone A, Morgante F. Long lasting effects of transcranial direct current stimulation on motor imagery. Neuroreport. 2004;15:1289–1291
    • View In Article
48. Wu T, Sommer M, Tergau F, et al. Lasting influence of repetitive transcranial magnetic stimulation on intracortical excitability in human subjects. Neuroscience Lett. 2000;287:37–40
    • View In Article
49. Di Lazzaro V, Oliviero A, Profice P, et al. Direct demonstration of intrahemispheric inhibition of the human motor cortex produced by transcranial magnetic stimulation. Exp Brain Res. 1999;124:520–524
    • View In Article
    • MEDLINE
    • CrossRef
50. Strafella AP, Ko JH, Monchi O. Therapeutic application of transcranial magnetic stimulation in Parkinson's disease: the contribution of expectation. Neuroimage. 2006;31:1666–1672
    • View In Article
    • MEDLINE
    • CrossRef
51. Strafella AP, Paus T, Fraraccio M, et al. Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain. 2003;126:2609–2615
    • View In Article
    • MEDLINE
    • CrossRef
52. Ziemann U, Hallet M, Cohen L. Mechanisms of deafferentation induced plasticity in human motor cortex. J Neurosci. 1998;18:7000–7007
    • View In Article
    • MEDLINE
53. Ziemann U. TMS induced plasticity in human cortex. Rev Neurosci. 2004;15:53–266
    • View In Article
54. Kinecht S, Henningsen H, Hohling P, et al. Plasticity of plasticity? Changes in the pattern of perceptual correlates of reorganization after amputation. Brain. 1998;121:717–724
    • View In Article
    • CrossRef
55. Sandyk R. Treatment with AC pulsed electromagnetic fields improve olfactory function in Parkinson's disease. Int J Neurosci. 1999;97:225–233
    • View In Article
    • MEDLINE
    • CrossRef
56. Hawkes CH, Shephard BC, Daniel SE. Is Parkinson's disease a primary olfactory disorder?. QJM. 1999;92:473–480
    • View In Article
    • MEDLINE
    • CrossRef
57. Leenders KL, Palmer AJ, Quinn N, et al. Brain dopamine metabolism in patients with Parkinson's disease measured with positron emission tomography. J Neurol Neurosurg Psychiatry. 1986;49:853–860
    • View In Article
    • MEDLINE
    • CrossRef
58. Müller A, Reichmann H, Livermore A, et al. Olfactory function in idiopathic Parkinson's disease (IPD): results from cross-sectional studies in IPD patients and long-term follow-up of de-novo IPD patients. J Neural Transm. 2002;109:805–811
    • View In Article
    • MEDLINE
    • CrossRef
59. Burkhard PR, Landis BN. Parkinsonism: the hyposmia and phantosmia connection. Arch Neurol. 2009;66:539
    • View In Article
    • CrossRef
60. Juckel G, Mendlin A, Jacobs BL. Electrical stimulation of rat medial prefrontal cortex enhances forebrain serotonin output: implications for electroconvulsive therapy and transcranial magnetic stimulation in depression. Neuropsychopharmacology. 1999;21:391–398
    • View In Article
    • CrossRef
61. Betarbet R, Zigova T, Bakay RA, et al. Dopaminergic and gabaergic interneurons of the olfactory bulb are derived from the neonatal subventricular zone. Int J Dev Neurosci. 1996;14:921–930
    • View In Article
    • MEDLINE
    • CrossRef
62. Panzanelli P, Homanics GE, Otterson OP, et al. Pre and post synaptic GABA a receptors at reciprocal dendrodendritic synapses in the olfactory bulb. Eur J Neurosci. 2004;20:2945–2951
    • View In Article
    • CrossRef
63. Brünig I, Sommer M, Hatt H, et al. Dopamine receptor subtypes modulate olfactory bulb γ-aminobutyric acid type a receptors. Proc Natl Acad Sci U S A. 1999;96:2456–2460
    • View In Article
    • MEDLINE
    • CrossRef
64. Olianas MC, Onali P. GABA_B receptor-mediated stimulation of adenylyl cyclase activity in membranes of rat olfactory bulb. Br J Pharmacol. 1999;126:657–664
    • View In Article
    • MEDLINE
    • CrossRef
65. Okutani F, Yagi F, Kaba H. GABAergic control of olfactory learning in young rats. Neuroscience. 1999;93:1297–1300
    • View In Article
    • MEDLINE
    • CrossRef
66. Nusser Z, Kay LM, Laurent G, et al. Disruption of GABA_A receptors on GABAergic interneurons leads to increased oscillatory power in the olfactory bulb network. J Neurophysiol. 2001;86:2823–2833
    • View In Article
    • MEDLINE