Olfactory hallucinations, or phantosmia, are hallucinations in which olfactory perceptions are conceived in the absence of a stimulus. It is a type of olfactory disorder from which parosmia, the tendency to incorrectly perceive a stimulating scent, is distinguished (1). Phantageusia, a hallucination of the taste modality, occurs when there is a perception of taste without a stimulus. Phantosmia and phantageusia are often comorbid especially when they are present alongside neurological disorders. Olfactory hallucinations primarily occur following nervous tissue damage to olfactory centers. Temporal lobe seizures are often the cause of such damage, but olfactory hallucinations may also be present with neurological disorders such as Schizophrenia, Alzheimer’s Disease, and Parkinson’s Disease (1). They may also occur with neurological traumas like intrancranial haemorrhages, as well as brain tumours and epilepsy (1). Phantosmia etiologies are not exempt from more mundane causes such as viral infections, i.e. sinus infection (1). Consistent exposure to airborne toxins like herbicides or pesticides can also affect the way smell is perceived (1). Furthermore, olfactory as well as gustatory hallucinations may have psychological origins. Studies approaching these subtypes from a neurobiological perspective indicate that the presence of phantageusia and phantosmia correlate with depressed levels of the GABA neurotransmitter in the central nervous system (2). The GABA levels in the CNS are proposed to have an inhibitory, as well as causal role in the expression of taste and olfactory hallucinations (2). Treatments for hallucinations of the olfactory sensory modality include both surgical and pharmacological options. In cases where phantosmia and phantageusia are accompanied by neurological disorders, pharmacological treatments that target these disorders, such as antidepressants, may also target the hallucinatory source (1).


Causes & Comorbid Disorders


Approximately 2/3 of all olfactory dysfunctions occur as a result of damage to the neuroepithelium of olfactory centers (1). Damages may arise from a multitude factors, including environmental as well as psychopathological origins, resulting in the olfactory hallucinatory experiences. Phantageusia remains a topic still mildly ventured; due to high comorbidity of taste hallucinations with olfactory hallucinations, the etiologies between the two have often been linked (7).

Viral Infections

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Coronal section at the level of the basal ganglia showing destruction of the left temporal lobe and swelling of the right parietal lobe as a results of Herpe Simplex Virus (Retrieved from http://jnnp.bmj.com/content/74/2/262.full); the temporal lobe has been implicated in olfactory processing

Viral infections, such as sinus infections, are potential sources for olfactory tissue damages leading to phantosmia, although often overlooked due to their commonality. When conditions are amicable, viruses may invade olfactory regions within the brain where they proceed to act neurotropically (1). The damages that arise from these neurotropic actions increase the probabilities for olfactory hallucinations. The susceptibility of a virally-infected individual varies according to diet, disease, drug, genetics or even age; these factors have been proposed to maybe increase or possibly inhibit mucociliary pathways, increasing the propensity of viruses to reach the brain (1). Some viruses become neurotropic once they enter the nasal cavity, the NWS strain of influenza being one (1). Viral infections known to cause such damages also include the common cold, polio, herpes simplex encephalitis, hepatitis, flu-like infections, as well as the Borna virus (1). It is more frequently upper respiratory infections that are implicated in such neurotropic related damages pertaining to olfactory hallucinations (1).



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Electron micrograph of olfactory bulb from a 4 weeks manganese-treated mouse showing a large degenerated neuron (Retrieved from http://www.scielo.org.ar/scielo.php?script=sci_arttext&pid=S0327-95452009000300007)



Toxins and Nanoparticles

Phantosmia-related damages may also arise from chemical toxins or nanoparticles in the environment (1). Chronic exposure to airborne chemicals such as herbicides, pesticides, solvents, and heavy metals can affect the olfactory experience, and so, olfactory perceptions (1). In fact, it has been shown that olfactory receptors are extremely efficient in picking up cadmium, chromium, manganese, and nickel, suggesting that the quick accumulation of these heavy metal toxins can in time produced deleterious effects (1). Airborne toxins have been implicated as potential etiological factors in neurodegenerative diseases, implying a possible origin of olfactory hallucinations as a symptom(1).








Psychological Origins

Olfactory hallucinations have also been regarded as a psychosomatic symptom present with delusional disorders, depression, and somatoform disorders (8). Studies have shown that olfactory hallucinations are, in fact, among the most prominent psychopathological correlates found in individuals diagnosed with delusional disorders (9). Olfactory and gustatory dysfunctions, although to lesser degree than other sensory modalities, occur as a symptom in schizophrenia as well (10). 1-25% of schizophrenic individuals report having olfactory hallucinations (10). Furthermore, there is a high occurrence of olfactory hallucination with tactile hallucinations in these individuals (10). Clinically, the occurrences of olfactory hallucinations concurrent with schizophrenia have been underrepresented; this is primarily because they have not been inquired about, and often overlooked (16).

Psychopathological symptom of Neurodegenerative Disease

Olfactory and taste hallucinations, although not prominently, often occur with neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease (1). It is likely a result of extended damage of neural tissue into olfactory and taste centers, an idea strengthened by studies showing that the olfactory bulb is among the first structures to be affected in Parkinson’s disease-associated pathologies (1). In addition, olfactory dysfunction is found to be proportional to plaques present in subfrontal and subtemporal brain regions of multiple sclerosis patients. Olfactory hallucinations may also appear in individuals with Creutzfeldt-Jakob disease, another neurodegenerative disease (1).

Other causes

Furthermore, susceptibilities for damage-related olfactory hallucinations vary in accordance with age, sex, as well as smoking, which can lead to damage of the olfactory mucosa (1, 10). Recent research has also implicated iatrogenic interventions such as chemotherapy in hallucinatory experiences of the olfactory sensory modality. (1, 4). Studies have shown that taste and smell function often changes with chemotherapy (4). Individuals usually experience hospital-related olfactory hallucinations, triggered by thoughts alone, in various settings different from that of the hospital (4). In addition, head traumas, cerebellar degeneration, tumours, primary headache disorders, intracranial hemorrhaging, as well as epilepsy have been shown to be accompanied by phantosmic experiences. (1, 3, 8, 14) However, most reported cases of olfactory hallucination are idiopathic. (3, 6) Studies monitoring the olfactory hallucinations arising from no detectable origin showed that more than five years after the first episodes, more than 50% of individuals no longer had olfactory hallucinations (3). Idiopathic phantageusia has been found to have decreased recovery rates in depressed individuals, proposing a potential link (3).

Furthermore, susceptibilities for damage-related olfactory hallucinations vary in accordance with age, sex, as well as smoking, which can lead to damage of the olfactory mucosa (1, 10). Recent research has also implicated iatrogenic interventions such as chemotherapy in hallucinatory experiences in the olfactory sensory modality (1, 4). Studies have shown that taste and smell function often changes with chemotherapy (4). Often individuals experience hospital-related olfactory hallucinations, triggered by thoughts alone, in various settings different from that of the hospital (4).


Proposed Neurobiological Mechanisms


One theory proposed regarding olfactory hallucinations is that they arise out of a discrepancy in the normal habituation of an odour (10). Rapid habituations lead to spontaneously “disappearing” smells; or habituation is slower and the individual perceives the smell long after it has gone, thus invoking what is imagined to be a hallucinatory experience (10).

Functional imaging technology has been used to reveal activation patterns in the brains of individuals who experience olfactory- and gustatory-specific hallucinations. Individuals with birhinal phantosmia (hallucinate foul odors) as well as global phantgeusia (hallucinate foul tastes) show greater left hemisphere activation than the right when imagining pleasant smells (5). This activation is reversed to normal activation patterns, greater left hemisphere activation, when the hallucinations are suppressed by the administration of neuroleptics (5). Furthermore, the studies suggest the activity of the anteriorfrontal and temportal cortices in olfactory hallucinations (5).

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FLASH brain fMRI of phantosmic patient after request to imagine her smell phantom. Images from left to right are anterior, middle, and posterior brain regions. Anterior: Marked activation in right superolateral frontal cortex, right cingulate, inferior frontal and posterolateral orbitofrontal cortex, bilaterally, and right temporal tip. Middle: Marked activation in superior frontal cortex and cingulate cortex, bilaterally, right lateral frontal cortex, right insular cortex, inferior temporal cortex, bilaterally with right > left, and near the right amygdala. Posterior: Marked activation in superior frontal cortex, bilaterally, cingulate cortex, bilaterally, right lateral and frontal temporal cortex, right inferior temporal cortex, and near the right hippocampus. (Henkin et al. 2000)

Changes in GABA levels in the CNS

Further fMRI studies have shown widespread brain activity associated with olfactory sensory distortions (2). With a focus on metabolites of the central nervous system, researchers have shown that certain relevant brain regions have depressed GABA levels in hallucinatory individuals compared to the control, primarily the anteriorfrontal and temporal lobes (2). The theory developed from these findings hold that GABA levels serve as a biochemical marker reflecting the sensory distortions of the olfactory and gustatory modalities (2) In support of this theory, upon application of the rTMS procedure on patients experiencing olfactory and/or gustatory hallucinations, sensory distortions are reversed (7). Repetitive transcranial magnetic stimulation is known to influence neurotransmitters like dopamine, GABA, biogenic amines, and others (7). Additionally, drugs that reverse GABA levels in hallucination-corresponding regions of the brain also show abolishment of sensory distortion (7, 2).


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The opthalamic and maxillary branches of the trigeminal nerve are involved in the innervations of the nasal cavity. (Retrieved from http://medical-dictionary.thefreedictionary.com/trigeminal)
Trigeminal System Involvement
Other theories have been propositioned regarding the involvement of the trigeminal systems. Many
odorants are able to innervate both the olfactory and trigeminal systems within the nasal cavity; information carried by both systems is eventually integrated (12). More specifically, the maxillary and opthalamic branches of the trigeminal nerve innervate the nasal cavity and are responsible for somatosensation (12, 13). Studies done on animal models show that the trigeminal nerve not only innervates olfactory epithelium, but can modulate olfactory responses to sensed odors (12). Therefore, both systems are involved in the global perception of smell (15). Investigation of this relationship under pathological conditions shows that trigeminal detection thresholds vary with the degree of olfactory disorders (11). A particular result of interest was that in anosmic individuals, who have lost their sense of smell, there was a much lower trigeminal activation (11). The conclusions of the study can be used to extrapolate how the trigeminal nerve may be involved in inducing phantosmia. Perhaps excessive trigeminal activation augments the sensitivity of the olfactory epithelium, and this in turn aids in the propagation of hallucinatory olfactory perceptions (13).







Surgical Resolution and Other Treatments


For migraine induced hallucinations, olfactory hallucinations are diminished with the administration of beta blockers or calcium channel blockers; prophylactic treatments for headaches also alleviate hallucinations (14). Migraine and epilepsy related phantosmia can be subsided with topiramate and gabapentin antieleptics (14). Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), has also been implicated in the treatment of phantosmia (8). Primarily used to treat depression, it not only improved mood, but also completely eradicated the olfactory hallucination that was concurrently present in patients administered the drug (8). Drugs like neuroleptics have also been shown to cease olfactory and gustatory hallucinations (5). There have also been cases where topical anaethestics, and sometimes sedatives, have alleviated olfactory hallucination (8).
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Percentage of patients who report disappearance, improvement, worsening or no change at all of idiopathic phantosmia more than 5 years after occurrence. (Landis et al. 2010)

Patients experiencing idiopathic olfactory hallucinations have found saline nose rinses, sleep, crying, forced inspiration, as well as sneezing, to sometimes aid in blocking the hallucinatory experience; although, these very methods, as reported, have the potential to set a olfactory hallucination in motion (8). Most cases of idiopathic phantosmia are spontaneously reversed without intervention (6).

Preliminary work done with repetitive transcranial magnetic stimulation has proven to be a promising method for relieving both patients experiencing phantosmia and phantageusia of hallucinations in their respective modalities (7). The procedure was applied to frontoparietal regions (7). More than 80% of rTMS subjects showed remarkable decreases in distortions as well as increased acuity (7). However, the maintained absence of hallucinations was dependent on sustained rTMS treatment (7). Transnasal removal of olfactory epithelium and olfactory bulbectomies have been used in extreme cases to alleviate phantosmia(1). In cases where phantosmia and phantageusia are accompanied by neurological disorders, pharmacological treatments that target these disorders, such as antidepressants, may also target the hallucinatory source(1).


Clinical Significance


Olfactory hallucinations are often considered a preceding symptom of psychopathologies such as Alzheimer’s disease and Parkinson’s disease, as well as epileptic seizures (8). Making these connections between pathologies and symptoms allows for early detection, diagnosis, and clinical intervention. It should be mentioned that the notion of olfactory hallucinations as a prognostic factor for Alzheimer’s and Parkinson’s disease is controversial (3, 10). Olfactory hallucinations can vary in characteristics depending on the other precise pathology it may present with (14). This is something clinicians should exploit in order to pinpoint developing cormorbid disorders as early as they can. For example, the profiles of hallucinations, regarding hedonics and duration, are different between migraine-relevant phantosmia and depression-related phantosmia (14). Furthermore the deviations in activation patterns of the brain imaged using fMRI technology can be used to help predict abnormal hallucinatory behaviours (5). If hallucinations are ‘preclinical’ markers, then using imaging to identify changing activation patterns allows for preventative measures to take place before the full-blown pathology has set in.
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Comparison of features of phantosmia in different syndromes. (Coleman et al. 2011)

Studies looking into idiopathic phantosmias have found that less that 5% of individuals progress into worse states of hallucination or other pathologies (3). These findings challenge the applicability of olfactory hallucination as a reliable prognostic marker of pathologies such as Parkinson’s diseases or even tumour formation. However, these findings are relevant from a counselling standpoint as it allows clinicians to provide the individuals experiencing olfactory hallucinations with information regarding outcomes and appropriate treatment if required (3, 6).Controversy over the prognostic capabilities of olfactory hallucinations aside, better olfactory hallucination probes should be designed for more efficient treatment (16). Negative olfactory sensation regarding one’s own body breeds depression, and a sense of hopelessness above the embarrassment of mentioning unpleasant odours (16). Individuals may purposefully or unintentionally neglect to mention hallucinatory symptoms, for this reason better probes should be generated.















References

  1. Doty, R. L. The Olfactory System and Its Disorders. Semin. Neurol. 29(1), 74-81 (2009)
  2. Levy, L. M., & Henkin, R. I. Brain gamma-aminobutyric acid levels are decreased in patients with phantaguesia and phantosmia demonstrated by magnetic resonance spectroscopy. Journal of Computer Assisted Tomography. 28(6), 721-727 (2004)
  3. Landis, B. N., Reden, J., & Haehner, A. Idiopathic phantosmia: outcome and clinical significance. ORL K Otorhinolaryngol Relat Spec. 72(5), 252-255 (2010)
  4. Bernhardson, B. M., Tishelman, C., & Rutgvist, L. E. Olfactory changes among patients receiving chemotherapy. Eur J Oncol Nurs. 13(1), 9-15 (2008)
  5. Henkin R. I., & Levy L. M. Lateralization of brain activation to imagination and smell of odors using functional magnetic resonance imaging (fMRI): left hemispheric localization of pleasant and right hemispheric localization of unpleasant odors. J Comput Assist Tomogr. 25(4), 493-524 (2001)
  6. Hummel, T., & Lotsch, J. Prognostic factors of olfactory dysfunction. Arch Otolaryngol Head Neck Surg. 136(4), 347-351 (2010)
  7. Henkin, R. I., Potolicchio, S. J., & Levy L. M. Improvement in smell and taste dysfunction after repetitive transcranial magnetic stimulation. Am J Otolaryngol. 32(1), 38-46 (2011)
  8. Landis, B. N., Croy, I., & Haehner, A. Long lasting phantosmia treated with venlafaxine. Neurocase. 18(2), 112-114 (2012)
  9. de Portugal, E., Gonzalez, N., Haro, J. M., Autonell, J., & Cervilla, J. A. A descriptive case-register study of delusional disorder. Eur Psychiatry. 23(2), 125-133 (2008)
  10. Stevenson, R. J., & Langdon, R. A preliminary investigation of olfactory function in olfactory and auditory-verbal hallucinators with schizophrenia, and normal controls. Cogn Neuropsychiatry. 1, 1-19 (2011)
  11. Frasnelli, J., Schuster, B., & Hummel, T. Olfactory Dysfunction affects thresholds to trigeminal chemosensory sensations. Neuroscience Letters. 468(3), 259-263. (2010)
  12. Brand G. Olfactory/trigeminal interactions in nasal chemoreception. Neurosci Biobehav Rev. 30(7), 908-917 (2006)
  13. Benemei, S., Eleonora R., & Geppetti, P. Trigeminal nerve and phantosmia in primary headaches. Cephalalgia. 32(1), 85 (2012)
  14. Coleman, E. R., Grosberg, B. M., & Robbins, M. S. Olfactory hallucinations in primary headache disorders: case series and literature review. Cephalalgia. 31(4), 1477-1489 (2011)
  15. Silver, W. L., Arzt, A. H., & Mason, J. R. A comparison of the discriminatory ability and sensitivity of the trigeminal and olfactory system to chem.. stimuli in the tiger salamander. J Comp Physiol A. 164(1), 55-66 (1988)
  16. Langdon, R., McGuire, J., Stevenson, J. R., & Catts, S. V. Clinical correlates of olfactory hallucinations in schizophrenia. Br J Clin Psychol. 50(2), 145-163 (2011)
  17. Henkin, R. I., Levy L. M., & Lin C. S. Taste and smell phantoms revealed by brain functional MRI (fMRI). J Comput Assist Tomogr. 24(1), 106-123 (2000)