Volumetric differences in the pituitary between drug-naïve and medicated male patients with obsessive–compulsive disorder

Objective

Obsessive–compulsive symptoms are induced or aggravated by stress, and the pituitary is a key component of the hypothalamic-pituitary-adrenal axis. We examined pituitary volume in drug-naïve and medicated male patients with obsessive–compulsive disorder (OCD).

Methods

Volumetric magnetic resonance imaging studies were conducted on 62 male control subjects, medicated male patients (N = 50) and drug-naïve male patients (N = 12) with OCD.

Results

Pituitary volume was significantly smaller in drug-naïve patients with OCD (464.97 ± 55.82 mm³) compared to medicated patients (577.84 ± 129.11 mm³, P = 0.004) and control subjects (543.04 ±113.70 mm³, P = 0.027), and no difference between control subjects and medicated patients (P = 0.174).

Conclusion

The results indicate that drug-naïve male patients with OCD exhibit decreased pituitary volume. This finding suggests that dysregulation of the HPA axis in OCD may influence pituitary volume. In addition, the increased pituitary volume in medicated patients may reflect the effect of drugs on the pituitary.     

Longitudinal volume changes of the pituitary gland in patients with schizotypal disorder and first-episode schizophrenia

An enlarged volume of the pituitary gland has been reported in the schizophrenia spectrum, possibly reflecting the hypothalamic-pituitary-adrenal (HPA) hyperactivity. However, it remains largely unknown whether the pituitary size longitudinally changes in the course of the spectrum disorders. In the present study, longitudinal magnetic resonance imaging (MRI) data were obtained from 18 patients with first-episode schizophrenia, 13 patients with schizotypal disorder, and 20 healthy controls. The pituitary volume was measured at baseline and follow-up (mean, 2.7 years) scans and was compared across groups. The pituitary volume was larger in the schizophrenia patients than controls at baseline, and both patient groups had significantly larger pituitary volume than controls at follow-up. In a longitudinal comparison, both schizophrenia (3.6%/year) and schizotypal (2.7%/year) patients showed significant pituitary enlargement compared with controls (− 1.8%/year). In the schizophrenia patients, greater pituitary enlargement over time was associated with less improvement of delusions and higher scores for thought disorders at the follow-up. These findings suggest that the pituitary gland exhibits ongoing volume changes during the early course of the schizophrenia spectrum as a possible marker of state-related impairments.     

Smaller pituitary volume in adult patients with obsessive–compulsive disorder

Aims:  Another structure in the obsessive–compulsive disorder (OCD) circuit may be the pituitary gland because of the fact that limbic–hypothalamic–pituitary–adrenal (LHPA) axis abnormality has been reported in patients with OCD. There has been only one prior study, however, concerning pituitary volumetry, in which the sample was a pediatric group. The purpose of the present study was therefore to investigate this in an adult OCD patient group using magnetic resonance imaging (MRI).
Methods:  Pituitary volume was measured in 23 OCD patients and the same number of healthy control subjects. Volumetric measurements were made on T1-weighted coronal MRI, with 2.40-mm-thick slices, at 1.5 T, and were done blindly.
Results:  A statistically significantly smaller pituitary volume was found in OCD patients compared to healthy controls (age and intracranial volume as covariates). With regard to gender and diagnosis, there was a significant difference in pituitary gland volume ( F  = 4.18, P  < 0.05). In addition, post-hoc analysis indicated near-significant difference in men with OCD as compared with women with OCD ( P  = 0.07) and significant difference between control men and control women ( F  = 10.96, P  < 0.001).
Conclusions:  Taking into consideration that the prior study found decreases in pituitary volume in pediatric patients with OCD as compared with healthy control subjects, future large MRI studies should investigate pituitary size longitudinally, with a careful characterization of hypothalamo-pituitary-adrenal (HPA) function in conjunction with anatomic MRI evaluation.     

The loudness dependence of the auditory evoked potential (LDAEP) in schizophrenia,bipolar disorder,major depressive disorder,anxiety disorder,and healthy controls

Background

Serotonergic dysfunction in schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, and healthy controls was evaluated by measuring the activity of the loudness dependence of the auditory evoked potential (LDAEP).

Methods

The 357 subjects who were evaluated comprised 55 normal controls, 123 patients with major depressive disorder, 37 with bipolar disorder, 46 with schizophrenia, 37 with panic disorder (PD), 31 with generalized anxiety disorder (GAD), and 28 with post-traumatic stress disorder (PTSD).

Results

LDAEP was significantly stronger in healthy controls than in patients with either bipolar disorder (p = 0.025) or schizophrenia (p = 0.008), and significantly stronger in patients with major depressive disorder than in those with bipolar disorder (p = 0.01) or schizophrenia (p = 0.03). LDAEP did not differ significantly between patients with major depressive disorder and healthy control subjects (p = 0.667), or between healthy control subjects and patients with anxiety disorder, including PD (p = 0.469), GAD (p = 0.664), and PTSD (p = 0.167).

Conclusion

The findings of the present study reveal that patients with major psychiatric disorders exhibit different strengths of LDAEP according to their serotonin-related pathology. Studies controlled for psychotropic medication, menstruation cycle, and smoking are needed.     

Increased pituitary volume in patients with established bipolar affective disorder

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been demonstrated in bipolar disorder (BD), but previous magnetic resonance imaging (MRI) studies of pituitary gland volume in BD have reported variable findings. In this MRI study we investigated pituitary volume in 26 patients with established bipolar I disorder (8 males and 18 females, mean age = 38.4 years) and 24 matched controls (7 males and 17 females, mean age = 38.7 years). The BD patients had a significantly larger pituitary volume as compared with controls, but there was no association between pituitary volume and illness duration, number of manic/depressive episodes, daily medication dosage, family history, or clinical subtype (i.e., psychotic and nonpsychotic). Pituitary volume was larger in females than in males for both groups. These results support previous neuroendocrine findings that implicate HPA axis dysfunction in the core pathophysiological process of BD.     

Pituitary volume in pediatric obsessive-compulsive disorder.

BACKGROUND: Abnormalities in the limbic-hypothalamic-pituitary-adrenal (LHPA) axis have been implicated in the pathogenesis of obsessive-compulsive disorder (OCD). To our knowledge, however, no prior study has measured pituitary gland volume in OCD. METHODS: Volumetric magnetic resonance imaging studies were conducted in 31 psychotropic drug-na?ve children (10 boys, 21 girls) aged 8-17 years and 31 case-matched healthy comparison subjects. RESULTS: Pituitary volume was significantly smaller in patients with OCD as compared with healthy control subjects (11% smaller). Smaller pituitary volume in patients with OCD was associated with increased compulsive but not obsessive symptom severity. Boys with OCD had smaller pituitary gland volumes compared with control boys (20% smaller). No significant differences in pituitary volume were observed between girls with OCD and control girls. Boys with OCD had significantly smaller pituitary volumes than girls with OCD (31% smaller), whereas control boys also had smaller pituitary gland volumes compared with control girls (21% smaller). CONCLUSIONS: These findings provide new evidence of reduced pituitary volume in pediatric OCD that seems to be more prominent in male patients. The observed alterations in pituitary volume are consistent with neuroendocrine studies that have reported abnormalities in the LHPA axis in OCD.     

Normal pituitary volumes in children and adolescents with bipolar disorder: a magnetic resonance imaging study

The volume of the pituitary gland in adults with bipolar disorder has previously been reported to be smaller than that of healthy controls. Such abnormalities would be consistent with the HPA dysfunction reported in this illness. We conducted a study of children and adolescents with bipolar disorder to determine whether size abnormalities in the pituitary gland are already present early in illness course. Magnetic resonance imaging (MRI) morphometric analysis of the pituitary gland was carried out in 16 DSM-IV children and adolescents with bipolar disorder (mean age+/-sd=15.5+/-3.4 years) and 21 healthy controls (mean age+/-sd=16.9+/-3.8 years). Subjects underwent a 1.5 T MRI, with 3-D Spoiled Gradient Recalled (SPGR) acquisition. There was no statistically significant difference between pituitary gland volumes of bipolar patients compared to healthy controls (ANCOVA, age, gender, and ICV as covariates; F=1.77, df=1,32, P=.19). There was a statistically significant direct relationship between age and pituitary gland volume in both groups (r=.59, df=17, P=.007 for healthy controls; r=.61, df=12, P=.008 for bipolar patients). No evidence of size abnormalities in the pituitary gland was found in child and adolescent bipolar patients, contrary to reports involving adult bipolar patients. This suggests that anatomical abnormalities in this structure may develop later in illness course as a result of continued HPA dysfunction.     

Blunted ACTH response to dexamethasone suppression-CRH stimulation in posttraumatic stress disorder

Previous studies have suggested that patients with posttraumatic stress disorder (PTSD) have an enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) system and a blunted ACTH response to corticotropin releasing hormone (CRH). The effects of two dexamethasone dosages (0.75 and 1.5 mg) on the ACTH and cortisol concentrations after CRH stimulation (100 μg) were studied in eight patients with PTSD and matched healthy control subjects. Compared to healthy subjects, patients with PTSD have a blunted ACTH response to CRH. Cortisol concentrations were only significantly influenced by dexamethasone dosage. Our results give further evidence for a central role of the pituitary in reflecting changes of the negative feedback sensitivity of the HPA system in patients with PTSD.     

Pituitary volumes in hypochondriac patients

To date, no study has examined the pituitary volumes in patients with hypochondriasis. In the present study, we evaluated pituitary volumes in patients with hypochondriasis and healthy controls. Twenty individuals with hypochondriasis (ten males, ten females), aged 20 to 48 years, and healthy controls were included into the study. The pituitary volumes were obtained. Volumetric measurements were made with T1-weighted coronal MRI images, with 2.4-mm-thick slices, at 1.5 T, and were done blindly. Volumetric measurements did not demonstrate group differences in the brain measurements, i.e., whole brain volume, white, and gray matter volumes (P > 0.05). We found significantly smaller pituitary volumes of the whole group of hypochondriac patients compared to healthy controls (age and ICV as covariates). To conclude, the results from the current investigation suggest that hypochondriac patients had smaller pituitary volumes compared with healthy controls. This could be the keystone to a better understanding of the neurobiological basis of hypochondriasis.     

Pituitary volume in neuroleptic-naïve schizophrenia: a structural MRI study

Abnormalities in the hypothalamic–pituitary–adrenal axis (HPA) have been implicated in psychosis. To our knowledge, no prior study has measured pituitary volume in a neuroleptic-naïve schizophrenic population. Herein, we present data exploring the volumetric differences in a sample of antipsychotic-naïve patients with a DSM-IV diagnosis of schizophrenia versus appropriately matched healthy controls.

Pituitary volumes were measured in 51 patients with schizophrenia (36 males, 15 females, mean age ± S.D.: 25.2 ± 7.4 years) and 55 healthy controls (30 males, 25 females; mean age ± S.D.: 25.2 ± 6.6 years) Measurements were conducted on 1.5 mm thick T1-weighted coronal images from a 1.5T scanner by two trained raters. Patients with schizophrenia had significantly smaller pituitary volumes than healthy control subjects (mean volume ± S.D. = 0.58 ± 0.14 cm³ and 0.66 ± 0.17 cm³ respectively; ANCOVA (using intracranial volume, gender and age as covariates), F = 6.81, df = 1, 101; p = 0.01). These findings provide new evidence of a smaller pituitary volume in neuroleptic-naïve patients with schizophrenia. The observed alterations in pituitary volume are consistent with neuroendocrine studies that have reported abnormalities in the HPA axis in psychosis. Similar volume reductions have been seen in other neuropsychiatric populations and may cut across diagnostic boundaries.     

Decreased pituitary volume in patients with bipolar disorder.

BACKGROUND: Neuroendocrinologic investigations in bipolar disorder have suggested abnormalities in pituitary function. However, few imaging studies have evaluated possible anatomical differences in this brain structure in mood disorder patients. Our aim was to examine potential abnormalities in pituitary volume in patients with bipolar and in a comparison group of patients with unipolar disorder. METHODS: We measured the volumes of the pituitary gland in 23 patients with bipolar disorder (mean +/- s.d. = 34.3 +/- 9.9 years) and 13 patients with unipolar disorder (41.2 +/- 9.6 years), and 34 healthy control subjects (36.6 +/- 9.6 years) using 1.5 mm thick T1-weighted coronal 1.5 T MRI images. All measurements were done blindly by a trained rater. RESULTS: Patients with bipolar disorder had significantly smaller pituitary volumes than healthy control subjects (mean volume +/- s.d. = 0.55 +/- 0.15 ml and 0.68 +/- 0.20 ml, respectively; ANCOVA, F = 8.66, p = 0.005), and than patients with unipolar disorder (0.70 +/- 0.12 ml, F = 5.98, p = 0.02). No differences were found between patients with unipolar disorder and healthy control subjects (F = 0.01, p = 0.91). CONCLUSIONS: To our knowledge, this is the first study that reports smaller pituitary volumes in bipolar disorder. Our findings suggest that detectable abnormalities in pituitary size are present in patients with bipolar disorder, which may reflect a dysfunctional HPA axis.     

Pituitary Volumes Are Reduced in Patients with Somatization Disorder

Objective

Despite of the suggested physiological relationship between somatoform disorder and disturbances in HPA axis function no volumetric study of pituitary volumes in somatization disorder has been carried out. Therefore, we aimed to use structural MRI to evaluate the pituitary volumes of the patients with somatization disorder.

Methods

Eighteen female patients with somatization disorder according to DSM-IV and same number of healthy controls were included into the study. All subjects were scanned using a 1.5-T General Electric (GE; Milwaukee, USA) scanner. Pituitary volume measurements were determined by using manuallly tracings according to standard antomical atlases.

Results

It was found significantly smaller pituitary volumes of the whole group of somatization patients compared to healthy (t=-3.604, p=0.001). ANCOVA predicting pituitary volumes demonstrated a significant main effect of diagnostic group (F=13.530, p<0.001) but TBV (F=1.924, p>0.05) or age (F=1.159, p>0.05). It was determined that there was no significant correlation between smaller pituitary volumes and the duration of illness (r=0.16, p>0.05) in the patient group.

Conclusion

In conclusion, we suggest that the patients with somatization disorder might have significantly smaller pituitary volumes compared to healthy control subjects.     

Pituitary volume in unaffected relatives of patients with schizophrenia and bipolar disorder

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity has been demonstrated in both schizophrenia and bipolar disorder, but the mechanisms underlying this abnormality are still unclear. Enlarged pituitary volume has been recently reported in patients with first episode psychosis and been interpreted as a consequence of an increased activation of the HPA axis. The aim of this study was to assess the contribution of familial liability to pituitary volume in schizophrenia and bipolar disorder. Pituitary volume may be an indirect measure of HPA axis activity. METHODS: MRI brain scans and measurements of pituitary volumes were obtained for 183 subjects: 26 patients with established schizophrenia or schizoaffective disorder, 44 of their unaffected first-degree relatives (22 familial schizophrenia, 22 non-familial schizophrenia), 29 patients with established bipolar disorder, 38 of their unaffected first-degree relatives, and 46 healthy comparison subjects. RESULTS: We found a significantly larger pituitary volume (effect size=0.7) in unaffected relatives of patients with schizophrenia compared with controls (p=0.002); the pituitary was even larger in relatives of patients with familial schizophrenia (effect size=0.8, p=0.005). We did not find a significant difference in pituitary volume when comparing the relatives of bipolar patients with controls. Among patients, those with schizophrenia who were receiving prolactin-elevating antipsychotics had an increased pituitary volume compared with controls (effect size=1.0, p=0.006). CONCLUSIONS: These results suggest that the larger pituitary volume previously reported in first episode schizophrenia could be partly due to a genetic susceptibility to over-activate the HPA axis.     

Coping behavior in patients with panic disorder

The purpose of the present paper was to investigate the role of coping behavior in patients with panic disorder (PD). This was done by evaluating three items of coping behavior (seeking of social support, wishful thinking and avoidance) in the Ways of Coping Checklist. The subjects consisted of 30 patients with PD (26 with agoraphobia). Coping behavior and the severity of PD was investigated at baseline and at 24 months (the final outcome). At baseline there were no gender differences in coping behavior. The severity of panic attacks significantly correlated with that of agoraphobia. The baseline severity of PD (panic attacks and agoraphobia) did not correlate with coping behavior. At the outcome assessment there was no significant correlation between the severity of panic attack and coping behavior. The severity of agoraphobia at final outcome and the coping behavior (seeking of social support) at baseline were significantly correlated. In the group that had remission in agoraphobia (the good outcome group), the severity of agoraphobia at baseline was significantly lower and the seeking of social support coping behavior was significantly higher than that of the poor outcome group. No significant difference in panic attack severity was noted between the good and poor outcome groups. Discriminant analysis revealed that seeking of social support coping behavior was a significant discriminant factor of agoraphobia. Although these are preliminary data, special coping behavior might be related to improvement of agoraphobia in patients with PD.     

Inverse relationship between thalamic and orbitofrontal volumes in obsessive–compulsive disorder

Volumetric magnetic resonance imaging (MRI) studies in obsessive–compulsive disorder (OCD) have reported a smaller volume of the orbitofrontal cortex (OFC) and a larger volume of the thalamus compared with healthy controls. Both of these brain regions are strongly connected; therefore, it may be hypothesized that cortical and thalamic alterations are related. Here, we investigated the relationship between thalamic and orbitofrontal volumes in OCD patients relative to healthy controls. MRI volumetric measurements of the thalamus and the OFC were obtained in 16 OCD patients without comorbidity and 16 comparison subjects matched for age, sex and educational level. Partial correlation analyses that controlled for intracranial volume (ICV) were performed to explore relationships between thalamic and OFC volumes in each group. In order to assess the specificity of this relationship, we conducted similar analyses of the anterior cingulate cortex (ACC) as a non-OFC cortical volume. Finally, by using data from previously published volumetric MRI studies, we conducted a meta-regression to explore the relationships between volume changes in these regions of interest. Results showed that thalamic volumes were significantly negatively correlated with OFC volumes in OCD patients (r = − 0.83, p < 0.001), but not in healthy subjects (r = − 0.15, p = 0.59). A significant relationship between thalamic and ACC volumes was found neither in the OCD patients (r = 0.03, p = 0.91) nor in the comparison subjects (r = − 0.23, p = 0.40). Furthermore, meta-regression analyses showed that previously reported volume changes in the thalamus were significantly correlated with OFC volume changes (r = − 0.71, p < 0.05), but not with ACC volume changes (r = 0.07, p = 0.86). Although our results do not allow for any causal relationship to be established, they suggest that structural alterations of both the thalamus and the OFC are inversely and specifically related in OCD.     

An MRI study of the superior temporal subregions in patients with current and past major depression

The superior temporal gyrus (STG), especially its lateral portion, and temporal pole (TP) both play a central role in emotional processing, but it remains largely unknown whether patients with major depressive disorder (MDD) exhibit morphologic changes in these regions. We delineated the STG subregions [planum polare (PP), Heschl gyrus (HG), planum temporale (PT), rostral STG, and caudal STG] and TP using magnetic resonance imaging in 29 currently depressed patients (mean age = 32.5 years, 7 males), 27 remitted depressed patients (mean age = 35.1 years, 9 males), and 33 age- and gender-matched healthy control subjects (mean age = 34.0 years, 12 males). Both current and remitted MDD patients showed a significant volume reduction of the left PT and bilateral caudal STG as compared with healthy controls. The TP volume did not differ between the groups. The right PT volume was negatively correlated with total score on the Beck Depression Inventory in the MDD patients as a whole. Medication, presence of melancholia, and comorbidity with anxiety disorders did not affect the TP and STG volumes. These findings suggest that the volume reduction of the STG, but not the TP, may represent enduring brain changes in MDD even after recovery from depression, but right STG volume may also be related to the severity of depressive symptoms.     

Smaller amygdala is associated with anxiety in patients with panic disorder

Aims:  Anxiety a core feature of panic disorder, is linked to function of the amygdala. Volume alterations in the brain of patients with panic disorder have previously been reported, but there has been no report of amygdala volume association with anxiety.
Methods:  Volumes of hippocampus and amygdala were manually measured using magnetic resonance imaging obtained from 27 patients with panic disorder and 30 healthy comparison subjects. In addition the amygdala was focused on, applying small volume correction to optimized voxel-based morphometry (VBM). State–Trait Anxiety Inventory and the NEO Personality Inventory Revised were also used to evaluate anxiety.
Results:  Amygdala volumes in both hemispheres were significantly smaller in patients with panic disorder compared with control subjects (left: t = −2.248, d.f. = 55, P  = 0.029; right: t = −2.892, d.f. = 55, P  = 0.005). VBM showed that structural alteration in the panic disorder group occurred on the corticomedial nuclear group within the right amygdala (coordinates [x,y,z (mm)]: [26,−6,−16], Z score = 3.92, family-wise error-corrected P  = 0.002). The state anxiety was negatively correlated with the left amygdala volume in patients with panic disorder (r = −0.545, P  = 0.016).
Conclusions:  These findings suggested that the smaller volume of the amygdala may be associated with anxiety in panic disorder. Of note, the smaller subregion in the amygdala estimated on VBM could correspond to the corticomedial nuclear group including the central nucleus, which may play a crucial role in panic attack.     

Personality traits in early phases of panic disorder: implications on the presence of agoraphobia, clinical severity and short-term outcome

OBJECTIVE: To explore the relations between personality traits using the Big Five model and presence of agoraphobia, clinical severity and short-term outcome in an unbiased clinical sample of never-treated panic disorder patients. METHOD: Panic disorder (PD) patients (n = 103) in the first stages of their illness were evaluated using the Neuroticism-Extraversion-Openness Five Factor Inventory of Personality (NEO-FFI) and were compared with a sample of healthy subjects. Severity was assessed by the Panic Disorder Severity Scale and the Clinical Global Impression Scales. Patients were evaluated after 8 weeks of naturalistic pharmacologic treatment with Selective Serotonin Reuptake Inhibitors. RESULTS: Panic disorder patients show more neuroticism than healthy subjects. Patients suffering from agoraphobia are more introverted than controls. Extraversion, in addition to gender and distress, during panic attacks allows to correctly classifying 72% of the cases of agoraphobia. CONCLUSION: Low scores in extraversion contribute to explain the presence of agoraphobia in panic disorder. Personality traits are neither related to clinical severity nor to short-term response to pharmacological treatment.     

Effect of pharmacotherapy on serum cholesterol levels in patients with panic disorder

Shioiri T, Fuji K, Someya T, Takahashi S. Effect of pharmacotherapy on serum cholesterol levels in patients with panic disorder. Acta Psychiatr Scand 1996: 93: 164–167. © Munksgaard 1996. It is unclear whether elevated cholesterol level is a complication of panic disorder (PD) or is associated with pharmacotherapy. We compared the total cholesterol (TC) level in 47 PD patients with that in 47 gender- and age-matched normal controls (NC), and we also examined the pre- and post-treatment TC levels. There was no sex difference in TC. Before pharmacotherapy, the mean TC level in the PD group (194.9 ± 39.6 mg/dl) was non-significantly higher than that in the NC group (190.5±26.7 mg/dl). The mean TC level in the PD group was significantly reduced following the pharmacotherapy (post-TC: 184.7± 31.0 mg/dl; t= 2.44, P<0.02), and the subgroup treated with alprazolam (n = 26) showed markedly significant decrease of TC after the treatment (t= 2.36, P<0.03). The TC level in the PD subgroup with agoraphobia (n= 24, 198.9 ± 37.9 mg/dl) was slightly higher than that in the group without agoraphobia (n= 23, 190.8±41.6 mg/dl). These findings suggest that there is a relationship between cholesterol levels and treatment in PD.     

Relationship between perfectionism,personality disorders and agoraphobia in patients with panic disorder

OBJECTIVE: In earlier reports, we found that perfectionism might be involved in the development and/or maintenance of agoraphobia in panic disorder. The present report extends this work by examining the relationship between perfectionism and comorbidity with personality disorders in panic disorder patients with agoraphobia (PDA) and those without agoraphobia (PD). METHOD: We examined comorbidity of personality disorders by Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II) and assessed perfectionism using multidimensional perfectionism scale in 56 PDA and 42 PD patients. RESULTS: The PDA group met criteria for at least one personality disorder significantly more often than the PD group. With stepwise regression analyses, avoidant and obsessive-compulsive personality disorders emerged as significant indicators of perfectionism in patients with panic disorder. CONCLUSION: These findings suggest that perfectionism in panic disorder patients may be more common in those with comorbid personality disorders, and may be an important target for preventive and therapeutic efforts.