Optogenetics Neuromodulation of the Nose.

Recently developed optogenetic technology, which allows high-fidelity control of neuronal activity, has been applied to investigate the neural circuits underlying sensory processing and behavior. The nasal cavity is innervated by the olfactory nerve and trigeminal nerve, which are closely related to common symptoms of rhinitis, such as impairment of smell, itching, and sneezing. The olfactory system has an amazing ability to distinguish thousands of odorant molecules at trace levels. However, there are many issues in olfactory sensing mechanisms that need to be addressed. Optogenetics offers a novel technical approach to solve this dilemma. Therefore, we review the recent advances in olfactory optogenetics to clarify the mechanisms of chemical sensing, which may help identify the mechanism of dysfunction and suggest possible treatments for impaired smell. Additionally, in rhinitis patients, alterations in the other nerve (trigeminal nerve) that innervates the nasal cavity can lead to hyperresponsiveness to various nociceptive stimuli and central sensitization, causing frequent and persistent itching and sneezing. In the last several years, the application of optogenetics in regulating nociceptive receptors, which are distributed in sensory nerve endings, and amino acid receptors, which are distributed in vital brain regions, to alleviate overreaction to nociceptive stimuli, has gained significant attention. Therefore, we focus on the progress in optogenetics and its application in neuromodulation of nociceptive stimuli and discuss the potential clinical translation for treating rhinitis in the future.

[Features of olfactory impairment connected with trigeminal nerve system]. / Osobennosti narusheniya obonyaniya v aspekte sistemy troinichnogo nerva.

Data on the state of sense of smell in patients who had a new coronavirus infection caused by the SARS-CoV-2 virus are currently reduced because of the impairment of the olfactory nerve system. There are practically no results in studies of disorders in the trigeminal nerve system. OBJECTIVE: Qualitative assessment of olfactory disorders after COVID-19 according to the system of olfactory and trigeminal nerves with a targeted assessment of the functional component of olfactory disorders. MATERIAL AND METHODS: We examined 40 patients aged 19 to 66 who had a coronavirus infection. All patients underwent neurological, otorhinolaryngological examinations, olfactometry, filled out the hospital anxiety and depression scale. RESULTS: Anosmia was diagnosed in 5 (12.5%) patients, hyposmia in 21 (52.5%) patients, and normosmia in 14 (35%) patients. Formed: the 1st group - 14 patients (35%) with normogram according to olfactometry; the 2nd group - 26 patients (65%) with anosmia/hyposmia. In the 1st group, disorders of the anxiety-depressive spectrum were significantly more common. In the 2nd group, a low identification of odors was found, lying in the spectrum of fresh, sharp, unpleasant, irritating, compared with sweet and pleasant or neutral, which indicates a predominant lesion of the trigeminal system. CONCLUSION: In patients with complaints of impaired sense of smell after undergoing COVID-19, the possible functional nature of anosmia/hyposmia should be taken into account, which requires the referral of such patients to psychotherapeutic specialists, and the possible entry of olfactory disorders into the 'trigeminal' spectrum.

Objective nasal airflow measures in relation to subjective nasal obstruction, trigeminal function, and olfaction in patients with chronic rhinosinusitis.

BACKGROUND: This study aimed to determine how nasal airflow measures and trigeminal function vary among patients with chronic rhinosinusitis (CRS) versus healthy controls and whether these measures are correlated with subjective nasal obstruction (SNO), olfactory function, and CRS control. METHODOLOGY: Participants included CRS patients and healthy controls. After a structured medical history, nasal airflow (peak nasal inspiratory flow [PNIF]; active anterior rhinomanometry [AAR]), trigeminal function (trigeminal lateralization test, CO2 sensitivity), and olfactory "Sniffin's Sticks" odor identification test) tests were performed. SNO ratings were also obtained. RESULTS: Sixty-nine participants were included (37 men, 32 women, mean age 51 years). There was no significant difference for objective nasal airflow between patients and controls, but CRS patients had worse SNO, trigeminal function, and olfaction compared to controls. SNO, but not objective nasal airflow tests, was negatively correlated with CO2 sensitivity and odor identification. CONCLUSION: The perception of nasal obstruction does not only depend on nasal airflow, but may also be modulated by trigeminal function and other factors. Thus, the role of objective nasal airflow measures as a sole method of functional nasal obstruction assessment in CRS remains limited.

Neuralgia in the occipital region associated with ipsilateral trigeminal herpes zoster: Three case reports.

BACKGROUND: Nerve fibers related to pain and temperature sensation in the trigeminal nerve territory converge with the upper cervical spinal nerves from the level of the lower medulla oblongata to the upper cervical cord. This structure is called the trigemino-cervical complex and may cause referred pain in the territory of the trigeminal or upper cervical spinal nerves. CASE SERIES: Here, we report three cases of paroxysmal neuralgia in the occipital region with mild conjunctivitis or a few reddish spots in the ipsilateral trigeminal nerve territory. The patients exhibited gradual progression of these reddish spots evolving into vesicles over the course of several days, despite the absence of a rash in the occipital region. The patients were diagnosed with trigeminal herpes zoster and subsequently received antiherpetic therapy. Remarkably, the neuralgia in the occipital region showed gradual amelioration or complete resolution before the treatment, with no sequelae reported in the occipital region. DISCUSSION: The trigemino-cervical complex has the potential to cause neuralgia in the occipital region, as referred pain, caused by trigeminal herpes zoster. These cases suggest that, even if conjunctivitis or reddish spots appear to be trivial in the trigeminal nerve territory, trigeminal herpes zoster should be considered when neuralgia occurs in the ipsilateral occipital region.

Instrumental assessment of pressure pain threshold over trigeminal and extra-trigeminal area in people with episodic and chronic migraine: a cross-sectional observational study.

BACKGROUND: Central and peripheral sensitization are characterized by widespread hyperalgesia that is manifested by larger pain extent area and reduction in pressure pain threshold (PPT). PPT decreases in patients with migraine not only over the trigeminal cervical complex but also throughout the body. METHODS: A cross-sectional study was adopted to assess the local and widespread hyperalgesia in chronic and episodic migraine patients respect to healthy controls. The guidelines of Andersen's were used to evaluate the PPT bilaterally over 3 muscles in the trigemino-cervical complex (temporalis, sub-occipitalis, trapezius) and over 1 muscle far from this area (tensor fasciae latae). RESULTS: Thirty subjects with episodic migraine (35.8 ± 2.82 years), 30 with chronic migraine (53.03 ± 19.79 years), and 30 healthy controls (29.06 ± 14.03 years) were enrolled. The interaction effect was present for the trapezius muscle with a significant difference between the right and the left side in episodic group (p = 0.003). A group effect was highlighted in all four muscles analyzed such as suboccipital (p < 0.001), temporalis (p > 0.001), trapezius (p < 0.001), and TFL (p < 0.001). PPT was usually higher in the control group than in the episodic group which in turn was characterized by higher PPT values than the chronic group. CONCLUSIONS: People with chronic and episodic migraine presented lower PPT than healthy controls both in the trigeminal and in the extra-trigeminal area. People with chronic migraine presented lower PPT than episodic migraine only in the trigeminal area. Temporalis and sub-occipitalis are the most sensitive muscles in people with chronic and episodic migraine.

Patients with COVID-19-associated olfactory impairment also show impaired trigeminal function.

OBJECTIVE: Next to olfactory function, the nose can also perceive chemestetic sensations mediated by the trigeminal nerve. While olfactory dysfunction as a symptom of COVID-19 is well described, there has been little research on the limitation of other nasal sensory inputs due to SARS-CoV-2 infection. The aim of this study was to determine possible limitations of nasal chemesthesis after COVID-19 infection by a psychophysiological diagnostic tool. METHODS: In 65 patients with a PCR-confirmed, former COVID-19 disease, olfaction was tested by means of a sniffin' sticks test, tasting by taste sprays and chemesthesis with a menthol dilution series. The subjective self-assessment of the patients was recorded via a questionnaire. RESULTS: We found a restriction of nasal chemesthesis and the extent correlated with the loss of smell, as well as with the values of the taste score, but not with subjective self-assessment. CONCLUSION: Not only the ability to smell and taste, but also nasal chemesthesis is affected by COVID-19.

Headache as a Symptom of COVID-19: Narrative Review of 1-Year Research.

PURPOSE OF REVIEW: Headache is a common symptom of COVID-19 with emerging literature being published on the subject. Although it may seem unspecific, scientific evidence has allowed a better definition of this headache type, revealing relevant associations with other COVID-19 symptoms and prognoses. We therefore sought to highlight the most remarkable findings concerning headache secondary to COVID-19, specifically focusing on epidemiology, characteristics, pathophysiology, and treatments. RECENT FINDINGS: The real prevalence of headache as a symptom of COVID-19 is still unclear ranging from 10 to 70%. Headache mainly has a tension-type-like phenotype, although 25% of individuals present with migraine-like features that also occur in patients without personal migraine history. This finding suggests that a likely pathophysiological mechanism is the activation of the trigeminovascular system. SARS-CoV-2 neurotropism can occur by trans-synaptic invasion through the olfactory route from the nasal cavity, leading to anosmia which has been associated with headache. SARS-CoV-2 protein has been found not only in olfactory mucosa and bulbs but also in trigeminal branches and the trigeminal ganglion, supporting this hypothesis. However, other mechanisms such as brain vessels inflammation due to SARS-CoV-2 damage to the endothelium or systemic inflammation in the context of cytokine storm cannot be ruled out. Interestingly, headache has been associated with lower COVID-19 mortality. No specific treatment for COVID-19 headache is available at present. Studies show that investigating COVID-19 headache represents an opportunity not only to better understand COVID-19 in general but also to advance in the knowledge of both secondary and primary headaches. Future research is therefore warranted.

SPECT imaging of cerebral blood flow changes induced by acute trigeminal nerve stimulation in drug-resistant epilepsy. A pilot study.

OBJECTIVE: To explore the cortical areas targeted by acute transcutaneous trigeminal nerve stimulation (TNS) in patients with drug-resistant epilepsy (DRE) using single photon emission computed tomography (SPECT). METHODS: Ten patients with DRE underwent brain SPECT at baseline and immediately after a 20-minute TNS (0.25 ms; 120 Hz; 30 s ON and 30 s OFF) applied bilaterally to the infraorbital nerve. The French Color Standard International Scale was used for qualitative analyses and z-scores were used to calculate the Odds Ratio (OR). RESULTS: At baseline global hypoperfusion (mainly in temporo-mesial, temporo-parietal and fronto-temporal and temporo-occipital areas) was detected in all patients. Following TNS, a global increase in cortical tracer uptake and a significant decrease in median hypoperfusion score were observed. A significant effect favoring a general TNS-induced increase in cortical perfusion (OR = 4.96; p = 0.0005) was detected in 70% of cases, with significant effects in the limbic (p = 0.003) and temporal (p = 0.003) lobes. Quantitative analyses of z-scores confirmed significant TNS-induced increases in perfusion in the temporal (+0.59 SDs; p = 0.001), and limbic (+0.43 SDs; p = 0.03) lobes. CONCLUSION: Short-term TNS is followed a global increase in cortical perfusion, namely in the temporal and limbic lobes. SIGNIFICANCE: The TNS-induced perfusion increase may reflect neurons' activity changes in cortical areas implicated in the epilepsy network.

Percutaneous Trigeminal Nerve Stimulation Induces Cerebral Vasodilation in a Dose-Dependent Manner.

BACKGROUND: The trigeminal nerve directly innervates key vascular structures both centrally and peripherally. Centrally, it is known to innervate the brainstem and cavernous sinus, whereas peripherally the trigemino-cerebrovascular network innervates the majority of the cerebral vasculature. Upon stimulation, it permits direct modulation of cerebral blood flow (CBF), making the trigeminal nerve a promising target for the management of cerebral vasospasm. However, trigeminally mediated cerebral vasodilation has not been applied to the treatment of vasospasm. OBJECTIVE: To determine the effect of percutaneous electrical stimulation of the infraorbital branch of the trigeminal nerve (pTNS) on the cerebral vasculature. METHODS: In order to determine the stimulus-response function of pTNS on cerebral vasodilation, CBF, arterial blood pressure, cerebrovascular resistance, intracranial pressure, cerebral perfusion pressure, cerebrospinal fluid calcitonin gene-related peptide (CGRP) concentrations, and the diameter of cerebral vessels were measured in healthy and subarachnoid hemorrhage (SAH) rats. RESULTS: The present study demonstrates, for the first time, that pTNS increases brain CGRP concentrations in a dose-dependent manner, thereby producing controllable cerebral vasodilation. This vasodilatory response appears to be independent of the pressor response induced by pTNS, as it is maintained even after transection of the spinal cord at the C5-C6 level and shown to be confined to the infraorbital nerve by administration of lidocaine or destroying it. Furthermore, such pTNS-induced vasodilatory response of cerebral vessels is retained after SAH-induced vasospasm. CONCLUSION: Our study demonstrates that pTNS is a promising vasodilator and increases CBF, cerebral perfusion, and CGRP concentration both in normal and vasoconstrictive conditions.

Trigeminal nerve electrical stimulation: An effective arousal treatment for loss of consciousness.

BACKGROUND: To determine if trigeminal nerve electrical stimulation (TNS) would be an effective arousal treatment for loss of consciousness (LOC), we applied neuroscientific methods to investigate the role of potential brain circuit and neuropeptide pathway in regulating level of consciousness. METHODS: Consciousness behavioral analysis, Electroencephalogram (EEG) recording, Chemogenetics, Microarray analysis, Milliplex MAP rat peptide assay, Chromatin immune-precipitation (ChIP), Dual-luciferase reporter experiment, Western blot, PCR and Fluorescence in situ hybridization (FISH). RESULTS: TNS can markedly activate the neuronal activities of the lateral hypothalamus (LH) and the spinal trigeminal nucleus (Sp5), as well as improve rat consciousness level and EEG activities. Then we proved that LH activation and upregulated neuropeptide hypocretin are beneficial for promotion of consciousness recovery. We then applied gene microarray experiment and found hypocretin might be mediated by a well-known transcription factor Early growth response gene 1 (EGR1), and the results were confirmed by ChIP and Dual-luciferase reporter experiment. CONCLUSION: This study illustrates that TNS is an effective arousal strategy Treatment for LOC state via the activation of Sp5 and LH neurons and upregulation of hypocretin expression.

Case report: 2 cases of cardiac arrest caused by rhino-cardiac reflex while disinfecting nasal cavity before endonasal transsphenoidal endoscopic pituitary surgery.

BACKGROUND: Trigeminal-cardiac reflex (TCR) is a brainstem vagus reflex that occurs when any center or peripheral branch of the trigeminal nerve was stimulated or operated on. The typical clinical manifestation is sudden bradycardia with or without blood pressure decline. The rhino-cardiac reflex which is one type of TCR is rare in clinical practice. As the rhino-cardiac reflex caused by disinfection of the nasal cavity is very rare, we report these two cases to remind other anesthesiologists to be vigilant to this situation. CASE PRESENTATION: This case report describes two cases of cardiac arrest caused by rhino-cardiac reflex while disinfecting nasal cavity before endoscopic transsphenoidal removal of pituitary adenomas. Their heart rate all dropped suddenly at the very moment of nasal stimulation and recovered quickly after stimulation was stopped and the administration of drugs or cardiac support. CONCLUSION: Although the occurrence of rhino-cardiac reflex is rare, we should pay attention to it in clinical anesthesia. It is necessary to know the risk factors for preventing it. Once it occurs, we should take active and effective rescue measures to avoid serious complications.

Photophobia: shared pathophysiology underlying dry eye disease, migraine and traumatic brain injury leading to central neuroplasticity of the trigeminothalamic pathway.

BACKGROUND: Photophobia is a potentially debilitating symptom often found in dry eye disease (DE), migraine and traumatic brain injury (TBI). METHODS: We conducted a review of the literature via a PubMed search of English language articles with a focus on how photophobia may relate to a shared pathophysiology across DE, migraine and TBI. RESULTS: DE, migraine and TBI are common conditions in the general population, are often comorbid, and share photophobia as a symptom. Across the three conditions, neural dysregulation of peripheral and central nervous system components is implicated in photophobia in various animal models and in humans. Enhanced activity of the neuropeptide calcitonin gene-related peptide (CGRP) is closely linked to photophobia. Current therapies for photophobia include glasses which shield the eyes from specific wavelengths, botulinum toxin, and inhibition of CGRP and its receptor. Many individuals have persistent photophobia despite the use of these therapies, and thus, development of new therapies is needed. CONCLUSIONS: The presence of photophobia in DE, migraine and TBI suggests shared trigeminothalamic pathophysiologic mechanisms, as explained by central neuroplasticity and hypersensitivity mediated by neuropeptide CGRP. Treatment strategies which target neural pathways (ie, oral neuromodulators, transcutaneous nerve stimulation) should be considered in patients with persistent photophobia, specifically in individuals with DE whose symptoms are not controlled with traditional therapies.

SUNCT/SUNA: Case series presenting in an orofacial pain clinic.

AIM: Little is known about short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). We present our experience with SUNCT/SUNA patients to aid identification and management of these disorders. METHODS: A retrospective review of patient records of one orofacial pain clinic was performed. Inclusion criteria was a diagnosis of SUNCT/SUNA confirmed with at least one follow-up visit. RESULTS: Six of the 2464 new patients seen between 2015-2018 met the selection criteria (SUNCT n = 2, SUNA n = 4). Gender distribution was one male to one female and average age of diagnosis was 52 years (range 26-62). Attacks were located in the V1/V2 trigeminal distributions, and five patients reported associated intraoral pain. Pain quality was sharp, shooting, and burning with two patients reporting "numbness". Pain was moderate-severe in intensity, with daily episodes that typically lasted for seconds. Common autonomic features were lacrimation, conjunctival injection, rhinorrhea, and flushing. Frequent triggers were touching the nose or a specific intraoral area. Lamotrigine and gabapentin were commonly used as initial therapy. CONCLUSIONS: Differentiating between SUNCT/SUNA does not appear to be clinically relevant. Presenting symptoms were consistent with those published, except 5/6 patients describing intraoral pain and two patients describing paresthesia.

Electroacupuncture on Trigeminal Nerve-Innervated Acupoints Ameliorates Poststroke Cognitive Impairment in Rats with Middle Cerebral Artery Occlusion: Involvement of Neuroprotection and Synaptic Plasticity.

Poststroke cognitive impairment (PSCI) is a severe sequela of stroke. There are no effective therapeutic options for it. In this study, we evaluated whether electroacupuncture (EA) on the trigeminal nerve-innervated acupoints could alleviate PSCI and identified the mechanisms in an animal model. The male Sprague-Dawley rat middle cerebral artery occlusion (MCAO) model was used in our study. EA was conducted on the two scalp acupoints, EX-HN3 (Yintang) and GV20 (Baihui), innervated by the trigeminal nerve, for 14 sessions, daily. Morris water maze and novel object recognition were used to evaluate the animal's cognitive performance. Neuroprotection and synaptic plasticity biomarkers were analyzed in brain tissues. Ischemia-reperfusion (I/R) injury significantly impaired spatial and cognition memory, while EA obviously reversed cognitive deterioration to the control level in the two cognitive paradigms. Moreover, EA reversed the I/R injury-induced decrease of brain-derived neurotrophic factor, tyrosine kinase B, N-methyl-D-aspartic acid receptor 1, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, γ-aminobutyric acid type A receptors, Ca2+/calmodulin-dependent protein kinase II, neuronal nuclei, and postsynaptic density protein 95 expression in the prefrontal cortex and hippocampus. These results suggest that EA on the trigeminal nerve-innervated acupoints is an effective therapy for PSCI, in association with mediating neuroprotection and synaptic plasticity in related brain regions in the MCAO rat model.

Central effects of erenumab in migraine patients: An event-related functional imaging study.

OBJECTIVE: To determine whether erenumab, a new monoclonal antibody to the calcitonin gene-related peptide (CGRP) receptor, exerts functional central effects in migraineurs by performing functional imaging scans on patients treated with erenumab. METHODS: We conducted an fMRI study on 27 patients with migraine using a well-established trigeminal nociceptive paradigm, examining patients before and 2 weeks after administration of the CGRP receptor antibody erenumab 70 mg. RESULTS: Comparing both visit days in all patients (n = 27) revealed that erenumab leads to a decrease in activation in the right thalamus (i.e., contralateral to the stimulated side), right middle temporal gyrus, right lingual gyrus, left operculum, and several clusters on both sides of the cerebellum. Furthermore, when responders (n = 9) and nonresponders (n = 8) of the respective same headache state were compared, we found a significant reduction of hypothalamic activation after the administration of erenumab in responders only (t = 4.78; contrast estimate 29.79 [90% confidence interval 19.53-40.05]). This finding of reduced hypothalamic activation was confirmed when absolute headache days was used as a regressor. INTERPRETATION: These findings suggest that erenumab may not be an exclusively peripheral migraine treatment but has additional central effects. Whether this is due to secondary changes after peripheral modulation of sensory input or indeed represents a direct central mode of action is discussed.

Modulation of mechanosensory vibrissal responses in the trigeminocervical complex by stimulation of the greater occipital nerve in a rat model of trigeminal neuropathic pain.

BACKGROUND: Stimulation of the occipital or trigeminal nerves has been successfully used to treat chronic refractory neurovascular headaches such as migraine or cluster headache, and painful neuropathies. Convergence of trigeminal and occipital sensory afferents in the 'trigeminocervical complex' (TCC) from cutaneous, muscular, dural, and visceral sources is a key mechanism for the input-induced central sensitization that may underlie the altered nociception. Both excitatory (glutamatergic) and inhibitory (GABAergic and glycinergic) mechanisms are involved in modulating nociception in the spinal and medullary dorsal horn neurons, but the mechanisms by which nerve stimulation effects occur are unclear. This study was aimed at investigating the acute effects of electrical stimulation of the greater occipital nerve (GON) on the responses of neurons in the TCC to the mechanical stimulation of the vibrissal pad. METHODS: Adult male Wistar rats were used. Neuronal recordings were obtained in laminae II-IV in the TCC in control, sham and infraorbital chronic constriction injury (CCI-IoN) animals. The GON was isolated and electrically stimulated. Responses to the stimulation of vibrissae by brief air pulses were analyzed before and after GON stimulation. In order to understand the role of the neurotransmitters involved, specific receptor blockers of NMDA (AP-5), GABAA (bicuculline, Bic) and Glycine (strychnine, Str) were applied locally. RESULTS: GON stimulation produced a facilitation of the response to light facial mechanical stimuli in controls, and an inhibition in CCI-IoN cases. AP-5 reduced responses to GON and vibrissal stimulation and blocked the facilitation of GON on vibrissal responses found in controls. The application of Bic or Str significantly reduced the facilitatory effect of GON stimulation on the response to vibrissal stimulation in controls. However, the opposite effect was found when GABAergic or Glycinergic transmission was prevented in CCI-IoN cases. CONCLUSIONS: GON stimulation modulates the responses of TCC neurons to light mechanical input from the face in opposite directions in controls and under CCI-IoN. This modulation is mediated by GABAergic and Glycinergic mechanisms. These results will help to elucidate the neural mechanisms underlying the effectiveness of nerve stimulation in controlling painful craniofacial disorders, and may be instrumental in identifying new therapeutic targets for their prevention and treatment.

Multisensory environmental sensitivity in patients with chronic tinnitus.

OBJECTIVE: The study aimed at investigating the sensitivity to noise and chemosensory environmental stressors as well as the relation to perceived stress, depression and anxiety in subjects with chronic tinnitus as compared to subjects without tinnitus. METHODS: We included 75 subjects with chronic tinnitus and 75 age and sex-matched subjects without tinnitus. Standardized questionnaires assessing the level of distress and impairment of quality of life caused by tinnitus, perceived level of stress, anxiety and depression, environmental noise and chemosensory sensitivity were used. A subgroup of 27 subjects with chronic tinnitus and 20 age-matched subjects without tinnitus underwent testing of olfactory function with the Sniffin' Sticks test and testing of intranasal trigeminal function using CO2 thresholds. RESULTS: Our data confirmed the increased environmental noise sensitivity (NSS) in patients with tinnitus. Furthermore, we observed an increased environmental chemosensory sensitivity (CSS), but no difference in measured chemosensory function. Subjects with tinnitus showed also significant higher levels of perceived stress, anxiety and depression and those symptoms partially correlated to CSS and NSS. Predictors of both NSS and CSS results were the presence / absence of tinnitus and high anxiety levels while neither stress nor depression were found as predicting variables. CONCLUSIONS: The results suggest that chronic tinnitus is related to a multisensory environmental hypersensitivity. Anxiety seems to be a predictor of this environmental vulnerability.