Evaluation of olfactory bulb volume and olfactory sulcus depth in patients with panic disorder and depressive disorder: An MRI study.

Background: Although some studies have shown decreases in the olfactory bulb (OB) volume and olfactory function in depressive disorder, there are no studies investigating OB volume in patients with panic disorder. Aim: The aim of this study was to investigate whether there was a change in OB volume and olfactory sulcus (OS) depth in patients with panic and depressive disorder when compared with the control group, and which group was more affected by comparing the two disease groups.
Methods: Data of 51 patients with panic disorder and 56 patients with depressive disorder were obtained by scanning the database of the hospital retrospectively. The control group consisted of 56 subjects without panic and depressive disorder. OB volume and OS depth measurements were performed on cranial magnetic resonance imaging (MRI).
Results: Bilateral OB volume of the panic and depressive disorder groups were significantly lower than those of the control group. The lowest volume was found in depressive patients. There was no significant difference between the groups with respect to OS measurements. When OB volume and OS depth differences between the genders were evaluated, a statistically significant difference was not determined.
Conclusion: Reduced OB volume was determined in both panic and depressive disorder patients, and clarification of these preliminary findings may contribute to the pathophysiology of panic and depressive disorders. Copyright:

INTRODUCTION

It has been known for some time that the olfactory bulb (OB) is affected by such neurological diseases as temporal lobe epilepsy,[1] multiple sclerosis,[2] Alzheimer’s disease,[3] Parkinson’s disease,[4] and finally migraine.[5] Recent studies, however, have presented strong evidence that OB involvement is not specific only to neurological diseases, and may even be a promising marker for psychiatric diseases.[67] The psychiatric diseases demonstrated to be associated with olfactory dysfunction include seasonal affective disorder,[8] mood disorders,[9] anorexia nervosa,[10] schizophrenia,[11] and panic disorder,[12] among which, depressive disorder is the most commonly studied disease in terms of its association with the olfactory system.

The olfactory system plays a much more important role in animals than humans, the relatively smaller sizes of human olfactory structures are said to be a result of evolutionary change. In contrast, the sense of smell has maintained its superiority in quadrupeds such as cats, dogs, and rodents due to its importance in vital behaviors such as feeding, reproduction, and threat.[13] However, the human OB is considered to be highly plastic, with changes in volume reflecting changes in olfactory sensitivity. Previous studies have identified reduced olfactory function and OB volume in depressive patients.[1415] The human OB sends robust projections into amygdaloid nuclei, hippocampus, orbitofrontal cortex, anterior cingulate cortex, and insular regions.[13] A decrease in olfactory input may disrupt the balance of the neuronal emotional processes[16] and thus may make people more prone to depression.

Although there are only limited studies exploring the association between the olfactory system and anxiety disorders, it is understood that the olfactory system is linked not only to depression but also anxiety. A previous study found that the removal of the olfactory organ in rats led to anxiety-like behaviors and increased the spontaneous neuronal firing rate in the basal amygdala.[17] Olfactory stimulation is frequently used to induce fear in animal experiments,[18] whereas, in humans, it has been demonstrated that odors trigger pathological anxiety reactions related to traumatic memories.[19] Specifically, fear-related odors have been shown to activate the neuronal regions such as the amygdala, cingulate cortex, insula, precuneus, and dorsomedial prefrontal cortex/inferior frontal gyrus that are related to panic disorder.[2021]

In a previous study, an impaired activity pattern was observed in the temporal lobe regions on electroencephalogram with olfactory stimulation in patients with panic disorder,[22] whereas another study identified olfactory-triggered panic attacks.[23] These results should not be considered surprising because the brain regions that undergo changes during panic disorder overlap with those involved in the olfactory system (amygdala, orbitofrontal cortex, insula, hippocampus, and thalamus).[2425]

The basis of the present study includes the identification of olfactory dysfunction in patients with panic disorder in previous studies; the fact that OB, which is considered to be a dynamic organ, exhibits volume changes in several psychiatric diseases; the lack of any study to date evaluating the volume of OB in panic disorder in literature, to our knowledge; and the fact that brain regions involved in the neuroanatomical model of the panic disorder overlap with those involved in the olfactory system. The present study investigates whether any change occurs in the OB volume and olfactory sulcus (OS) depth in patients with panic disorder and depressive disorder when compared with the control group, and which group is more affected through a comparison of the two disease groups. To our knowledge, there is no such study evaluating the volume of OB in panic disorders in the literature.

METHODS

Subjects

The study data were collected via a retrospective review of the records of patients who presented to a university hospital between 2015 and 2019. The study was approved by the local ethics committee (protocol number: 2017-KAEK-189_2019.06.26_08) and approval was obtained from the hospital administration regarding the use of recorded patient data. The consent of the patients was obtained. The magnetic resonance (MR) images recorded on the hospital’s picture archiving and communication system (PACS) were reviewed retrospectively, and patients diagnosed with panic disorder and depressive disorder were included in the study. These patients have symptoms such as dizziness, lightheadedness, fainting, and numbness, and those who have had magnetic resonance imaging (MRI) taken to eliminate the causes of organic disease. As a result of the MR images and examination of these patients, an organic pathology was not detected. The study included 51 patients with a diagnosis of panic disorder with and without agoraphobia and 56 patients with a diagnosis of major depressive disorder, who were found to be eligible following the application of the inclusion and exclusion criteria. Diagnoses were made according to the DSM-5 criteria.[26] The same procedure was applied to the control group through a retrospective review of the PACS by the radiology department. Accordingly, the study included 56 subjects without any psychiatric diseases who had presented to the hospital with such symptoms as vertigo and headache; however, in whom MR images and physical examination revealed no pathological findings. To exclude possible psychopathology in the healthy control group, individuals were contacted by telephone and questioned in terms of psychiatric symptoms by the first author. Those who were thought to have a psychiatric diagnosis were not included in the study.

The clinical and demographic data of both the patient and the control groups were also collected retrospectively.

The inclusion criteria were having been diagnosed with panic disorder or depressive disorder and aged between 18 and 50 years, whereas the exclusion criterion was having been diagnosed with a psychiatric disease other than depression or panic disorder, previous trauma or surgery history, septal deformity, sinonasal tumor, sinonasal infections, sinonasal polyposis, marked nasal deformity, multiple sclerosis, epilepsy, and Parkinson’s disease.

MRI procedure

The MR images were taken using a 1.5 Tesla system and a standard quadrature head coil (Initial Ingenia model no: 7813–72; Philips Medical Systems, Netherlands, Tilburg). Coronal sections were placed perpendicular to a virtual midline between the nasal septum and cerebral falx. Coronal T2-weighted sections were obtained using the following parameters: 1000/100 ms (TR/TE); section thickness, 5 mm; matrix, 384 × 239; FOV, 230 × 184 mm; and in-plane pixel resolution, 0.5 × 0.5 mm. OB was observed as a hypointense structure surrounded by hyperintense cerebrospinal fluid. OB was detected in a tangent plane toward the posterior of the bulbus oculi[27] and was displayed manually through T2-weighted coronal slices. Volume data were expressed in cubic centimeters calculated from the structural thickness and plane area.[4] OS depth was measured from a selected slice of the coronal images. To ensure the same slice positions for this measurement, a coronal slice tangent to the posterior of the bulbus oculi was used. No structural abnormalities or distinct lesions were identified in the patient or the control groups. OB and OS measurements of all data (patients and healthy group) were performed by the same radiologist who was blind to the group category.

Statistical analyses

The data were analyzed with “The Statistical Package for Social Sciences for Windows” (SPSS v18) software. Categorical variables are expressed as percentages and numbers, and the Chi-square test was used for analysis. Continuous variables are given using mean and standard deviations. One-way analysis of variance (ANOVA) was used for comparison between the groups after the Kolmogorov–Smirnov test was run to evaluate whether the variables show normal distribution. In cases where there was a significant difference between the groups, posthoc comparisons were performed using Tukey or Tamhane’s T2 tests according to variance homogeneity. Levene’s test was used to assess the homogeneity of the variances. Mann–Whitney U test was used to compare OB volume and OS depth differences according to gender in the groups. The associations between the variables were investigated using the Pearson or Spearman test. The level of statistical significance was set at P < 0.05.

RESULTS

Clinical and demographic characteristics of patients and controls are summarized in Table 1. There was no significant difference between the groups in terms of age and gender (P = 0.383, P = 0.741, respectively). Patients with panic disorder and depressive disorder were similar in terms of disease duration and drug use (P = 0.756, P = 0.342, respectively).

Table 1

Clinic and demographic features of the groups

	Panic disorder (n=51) Number (%) or Mean±SD	Depressive disorder (n=56) Number (%) or Mean±SD	Control group (n=56) Number (%) or Mean±SD	P
Age	36.49	36.41	38.23	0.383a
Gender
Male	21 (41.2%)	19 (33.9%)	21 (37.5%)	0.741b
Female	30 (58.8%)	37 (66.1%)	35 (62.5%)
Duration of disease (years)
<1	34 (69.4%)	40 (72.7%)		0.756b
1-5	13 (24.5%)	11 (20%)
5-10	4 (6.1%)	3 (5.5%)
>10	0	2 (1.8)
Drug intake
SSRIs	13 (25%)	17 (30.4%)		0.342b
SNRIs	8 (14.6%)	4 (7.1%)
Combined	0	2 (3.6%)
Absent	30 (60.4%)	33 (58.9%)

n=number of subjects; SD: standard deviation; a: one-way variance analysis (ANOVA); b: Chi square test; SSRIs: selective serotonin reuptake inhibitors; SNRIs: serotonin–norepinephrine reuptake inhibitors

When the groups were compared in terms of OB volume and OS depth [Table 2]; in both the depressive disorder and panic disorder groups, there was a significant decrease in bilateral OB volume compared with the control group (P < 0.001). The highest volume decrease was found in depressive patients [Figure 1]. There was no significant difference between the groups in respect to OS measurements (P > 0.05).

Table 2

Comparison of ROBV, LOBV, ROSD, and LOSD values between groups

	PD Mean±SD	DD Mean±SD	Control group Mean±SD	F	P	Post-hoc test (P-values) PD vs. Control group	DD vs. Control group	PD vs. DD
ROBV	44.01±4.60	39.79±5.38	47.13±4.04	34.229	0.000	0.002	0.000	0.000
LOBV	43.89±4.29	39.99±4.98	47.76±3.84	43.552	0.000	0.000	0.000	0.000
ROSD	7.30±0.56	7.32±0.80	7.35±0.65	0.079	0.924	0.959	0.996	0.997
LOSD	7.30±0.51	7.34±0.66	7.46±0.59	1.086	0.340	0.342	0.529	0.934

ROBV: right olfactory bulb volume, LOBV: left olfactory bulb volume, ROSD: right olfactory sulcus depth, LOSD: left olfactory sulcus depth, PD: panic disorder, DD: depressive disorder. F: one-way analysis of variance (ANOVA)

Figure 1

Distribution of the left and right olfactory bulb volume among the groups. ROBV: Right olfactory bulb volume. LOBV: left olfactory bulb volume

When OB volume and OS depth differences between the genders were evaluated, it was determined that the two measurements were lower in both panic and depressive disorder groups. However, the difference was not statistically significant (for all, P > 0.05) [Table 3].

Table 3

Gender differences of ROBV, LOBV, ROSD, and LOSD values in panic disorder and depression groups

Panic disorder group	Mean rank Male (n=21)	Mean rank Female (n=30)	P
ROBV	30.10	23.13	0.10
LOBV	30.40	22.92	0.077
ROCD	27.36	25.05	0.585
LOCD	27.19	25.17	0.632
Depressive disorder group	Male (n=19)	Female (n=37)	P
ROBV	31.08	27.18	0.396
LOBV	31.21	27.11	0.373
ROCD	30.42	27.51	0.528
LOCD	29.92	27.77	0.640

ROBV: right olfactory bulb volume, LOBV: left olfactory bulb volume, ROSD: right olfactory sulcus depth, LOSD: left olfactory sulcus depth. P: Mann–Whitney U test

As shown in Table 4, the relationship between right OB volumes, left OB volume, right OS depth, left OS depth, age, and disease duration was analyzed with Pearson and Spearman correlation analysis. The right and left OB volumes were correlated with each other (r = 0.958 for the panic disorder group, 0.891 for the depressive disorder group, P < 0.001 for both disease groups). There was also a significant positive correlation between the right and left OS measurements (r = 0.777 for the panic disorder group, 0.883 for the depressive disorder group, P < 0.001 for both disease groups). As seen in Table 4, no significant correlation coefficients were identified between age and disease duration, OB volume, and OS measurements in both depressive and panic disorder groups.

Table 4

Relationship between ROBV, LOBV, ROSD, LOSD, age, and disease duration

Panic disorder group	LOBV	LOSD	Age	Duration of disease
ROBV	r=0.958*		r=−0.079	rho=−0.020
	P=0.000		P=0.583	P=0.894
LOBV			r=−0.040	rho=−0.011
			P=0.781	P=0.941
ROSD		r=0.777	r=−0.033	rho=−0.083
		P=0.000	P=0.820	P=0.570
LOSD			r=0.046	rho=−0.232
			P=0.750	P=0.109
Depressive disorder group	LOBV	LOSD	Age	Duration of disease
ROBV	r=0.891*		r=0.155	rho=0.140
	P=0.000		P=0.253	P=0.307
LOBV			r=0.251	rho=0.185
			P=0.062	P=0.175
ROSD		r=0.883*	r=0.016	rho=0.014
		P=0.000	P=0.908	P=0.918
LOSD			r=0.106	rho=0.072
			P=0.437	P=0.600

r: Pearson correlation coefficient, rho: Spearman correlation coefficient, ROBV: right olfactory bulb volume, LOBV: left olfactory bulb volume, ROSD: right olfactory sulcus depth, LOSD: Left olfactory sulcus depth

DISCUSSION

The present study found significantly decreased OB volumes bilaterally in both patients with panic disorder and depressive disorder when compared with the control group, with the highest decrease identified in patients with depressive disorder. This finding is consistent with previous studies in the literature in which decreased OB volume and olfactory sensitivity were identified in patients with depressive disorder.[1428]

It is still unclear whether the reduced OB volume is the cause or the consequence. Olfactory bulbectomized animals were found to have reduced brain plasticity, and the reduced hippocampal neurogenesis reversed after antidepressant treatment.[2930] In addition, an increased risk of depressive symptoms in people who have lost their sense of smell or who were born without a sense of smell has been detected.[31] There have also been studies reporting that a change in OB volume is a predisposing factor for depression.[6] Negoias et al. found OB volume to be associated with treatment response in patients with depression, and also identified significantly lower OB volumes in patients who were unresponsive to treatment. The authors observed no changes in OB volume during follow-up and concluded that OB volume was a biologically predisposing factor for the development or continuation of depression and that it prevents therapeutic response.[16]

There have been only limited studies on panic disorders to date. The study by Clepce et al.[32] found that patients with anxiety disorder exhibited poorer performance in olfactory discrimination tests than the control group although the authors did not place any specific emphasis on panic disorder. Burón et al.[33] comparing patients with panic disorder and control subjects identified a lower olfactory detection threshold, increased reactivity to odors, and a higher level of olfactory awareness in patients with panic disorder. It is possible that this increased olfactory function may be a pre-existing marker that promotes disease onset. Another study reported increased acoustic startle reflex due to amygdala disinhibition in bulbectomized animals, along with increased sensitivity to stressors.[34] OB sends direct connections to the piriform, entorhinal, and parahippocampal regions, and the amygdala and the stria terminalis,[35] and a disconnection results in the disinhibition of the amygdala. The decreased OB volume detected in patients with panic disorder in the present study may be considered as an indicator of this.

A previous study involving patients with depressive disorder, somatoform disorder, substance-use disorders, and eating disorders determined that depressive disorder has the strongest association with OB.[6] Similarly, the present study found that the decrease in OB in patients with depressive disorder is greater than that seen in patients with panic disorder. Asal et al.[28] detected a decreased OB volume in patients with anxiety and depressive disorder, but made no distinction between those with anxiety and panic disorders, evaluating both within the same group. The present study may be considered significant in its demonstration for the first time of decreased OB volume in patients with panic disorder.

The present study identified no significant difference between bilateral OS measurements in any of the patient groups when compared with the control group. The literature contains a few studies assessing OS measurements in psychiatric diseases. Asal et al.[28] identified a smaller left OS depth in the anxiety/depression group than in the control group although it should be noted that the number of patients with anxiety and depressive disorder involved in that study was only 37, and the groups were also unmatched in terms of gender. Hummel et al.[27] found OS depth on the left side to be associated with the olfactory function, but could not establish the same association for the right side. It was also shown that patients with current or past major depression have a narrower OS, and sulcus depth has been found to be associated with post-remission residual depressive symptoms.[36]

Although in the present study, lower OB volume and OS depth were identified in women among patients both with panic disorder and depressive disorder, the difference was not statistically significant. In another study involving 58 male and 67 female participants, a lower OB volume was noted in women,[37] but despite this lower OB volume, OB performance is reported to be better in women.[38] Although this finding indicates the presence of a gender difference in OB function, there is a need for future studies involving a higher number of patients.

Concurring with previous studies, the right and left OB volumes, and the right and left OS depths in the present study were found to be associated with each other in both disease groups.[2837] Contrary to studies reporting decreased OB volume with age, the present study identified no such association between age and neither OB volume nor OS depth in either the panic or depressive disorder groups.[37] In contrast to a previous study making an assessment over a wide age range of 19–79 years, the present study involved subjects aged between 18 and 50 years, and this difference is likely to have an effect on the obtained results. Because it is believed that the right and left OB volumes remain stable until the fourth decade of life in both men and women and start to decrease in the sixth and seventh decades.[37]

The present study identified no association between disease duration and neither OB volume nor OS depth. To the best of our knowledge, there have been no studies to date evaluating the duration of panic disorder and changes in OB volume and OS depth. Similarly, the OB has been reported to be related to disease duration in patients with depressive disorder although this study identified the strongest association in the older age group (above 50 years).[6] The exclusion of individuals over the age of 50 may have influenced the results of the present study.

The present study identified no association between drug use and OB volume and OS depth, and this finding seems to be consistent with the literature. In a study involving patients with panic disorder, it was found that drug use has no effect on olfactory measurements.[12] In another study involving depressive patients, no changes in OB volume were observed after psychotherapy in all patients, including those in the responders.[17]

The present study has some limitations. First of all, a more detailed analysis could not be performed, as some data, such as the severity of the disease, the number of previous attacks, and the duration of drug use were not recorded, and could not be garnered due to the retrospective nature of the study. The impact of smoking in the patient and control groups was also not taken into consideration; however, previous research found that smoking had no effect on OB volume.[1233] Matching the patients and control subjects in terms of age and gender and the elimination of the age effect through the exclusion of participants above the age of 50 years may be considered the strengths of the present study.

In conclusion, to our knowledge, this is the first study to identify a significant decrease in OB volume in panic disorder when compared with a control group. When patients with panic disorder and those with depressive disorders were compared, the highest decrease was observed in patients with depressive disorder. No significant difference was noted in OS measurements. Clarification of these preliminary findings may contribute to the pathophysiology of panic and depressive disorders. Accordingly, new treatment techniques, such as olfactory conditioning[39] and olfactory training,[40] may be considered as an option in the treatment of such patients. We believe that future prospective studies involving a wider series, minimizing the limitations and examining the correlation with drug doses, will contribute significantly to the literature, enlightening the role of OB in psychiatric diseases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.