Sinusoidal Galvanic Vestibular Stimulation for Neurogenic Orthostatic Hypotension / Syncope

Neurogenic orthostatic hypotension occurs in a significant number of people and has no effective treatment. Neurogenic orthostatic hypotension is associated with intermittent episodes of fainting which can be debilitating for the patients. Using sinusoidal galvanic vestibular stimulation, an oscillating current between the two ears, collaborators have discovered an effective technique to habituate anesthetized rats that develop vasovagal responses. The investigators propose to determine whether a similar use of sinusoidal galvanic vestibular stimulation can eliminate or alleviate neurogenic orthostatic hypotension and the associated syncope in susceptible human subjects. If so, then sinusoidal galvanic vestibular stimulation, which is safe and widely used to study muscle sympathetic nerve activity, can be used in humans, who have a history of syncope and a positive tilt test to habituate vasovagal responses. Habituation will be accomplished using repetitive periods of sinusoidal galvanic vestibular stimulation in two 30min sessions three times/week for 2 weeks. Similar 1 hour sessions are routinely used by others when activating muscle sympathetic nerve activity with sinusoidal galvanic vestibular stimulation without harm to the subjects. The 30 min periods were chosen because this was effective in producing habituation of vasovagal responses. The habituating stimulus will be given by applying paste electrodes over the mastoid processes and plugging the leads into a battery driven-stimulus box, which when activated by a switch, will provide a very low frequency bipolar, ± 2 mA, 0.025 Hz oscillating current sinusoidal galvanic vestibular stimulation between the mastoids. Subjects will be seated during the stimulation. The onset and end of the stimulation period will be denoted by tones, and the subjects will be free to watch television, read, or listen to music while they are being stimulated. The effectiveness of the habituation will be determined in several ways: 1) Subjects will keep a history of the number of episodes of syncope in the inter-test intervals. 2) They will have tilt tests at the beginning and end of habituation. 3) Their blood pressure and heart rate will be recorded and the investigators will determine if there is a loss of low frequency (0.025 Hz) oscillations, which the investigators have found in animal models to disappear when the animals are habituated. 4) Habituation should be accompanied by an increase in heart rate to counteract the fall in blood pressure.

Syncope is a highly prevalent condition affecting 42% of the population at some point in life. Physical injury occurs with syncopal events and the danger of injury becomes more prevalent with age. Syncope accounts for 3% of visits to emergency departments and 6% of all admissions to hospitals. For patients with frequent recurrent syncope, psychosocial impairment has an estimated adverse impact on 33% of the assessed aspects of daily life. There is also a large economic impact, with an estimated $2.4 billion annual cost, mostly due to hospitalizations.

Neurogenic orthostatic hypotension (nOH) results from impaired arterial vasoconstriction that normally is mediated by the baroreflex in response to gravitational pooling of blood. The characteristic findings in nOH are a drop in systolic blood pressure (SBP) of 20 mmHg or more, or a drop in diastolic blood pressure (DBP) of 10 mmHg or more, in response to standing or head-up tilt. What distinguishes nOH from other causes of orthostatic hypotension, such as vasovagal syncope or dehydration, is a blunted compensatory heart rate increase (\<15 BPM). nOH accounts for 15% of syncope in the general population and 24% of such cases in emergency room setting. The autonomic failure that precipitates nOH may result from α-synuclein protein deposits in central glial cells (multiple system atrophy) or in postganglionic autonomic neurons when associated with Parkinson's disease or primary autonomic failure. Secondary causes of autonomic failure include diabetic neuropathy and other autoimmune conditions that selectively target the peripheral autonomic nerves.

There is currently no standard of care for people suffering from syncope. Several treatment options have been explored, including beta blockers, corticosteroids, and pacemakers, but none of these have been more effective than placebo. The most promising therapy to date has been repeated static head-up tilts. Vestibulo-sympathetic reflex (VSR) is a term used for the redistribution of blood by vestibular stimulation through the actions of the sympathetic nervous system. 60° static head-up tilt activates otolith and body tilt receptors, which produce cardiovascular changes through the VSR. Using repeated static head-up tilts, "syncope-sensitive" patients were repetitively tilted 60° for periods of time. This was shown to habituate the (VSR) and reduce or eliminate syncope in some cases. However, while it was possible to habituate some subjects with head-tilts, the habituation techniques were too tedious and impractical to be effective in the general population. If there were a less tedious procedure that activated the vestibular system, it could be used to habituate syncope through the VSR.

Sinusoidal galvanic vestibular stimulation (sGVS) activates the otolith system. Blood pressure (BP) and heart rate (HR) have been studied in vasovagal responses in isoflurane-anesthetized Long-Evans rats during sinusoidal galvanic vestibular stimulation (sGVS) and nose-up tilt. In these studies, susceptible rats developed synchronous ≈20-50 mmHg decreases in BP and ≈20-50 bpm decreases in HR over seconds that recovered slowly over minutes in response to repeated vestibular (otolith) stimulation. The sudden decrease in BP and HR, followed by the slower return to pre-stimulus values, are the main components of the vasovagal response that underlie and generate vasovagal syncope. It was found that rats previously susceptible to the induction of vasovagal responses progressively lost their susceptibility as testing continued. The loss of susceptibility to vasovagal responses indicates that the rats were habituated through activation of the VSR, using sGVS. It was concluded that habituation was successful by blocking the occurrence of low frequency oscillations in BP and HR in rats, which are thought to be the critical elements in initiating vasovagal responses. The loss of susceptibility in this study was associated with a rise in HR to oppose the fall in BP. These findings concurred with previous studies demonstrating habituated responses with static head-up tilts. Why these findings were not supported by some other studies, remains unclear; but one author suggested the reason for their findings in humans was that static head-up tilts were sufficiently tedious that it resulted in non-compliance.

The strategy for addressing nOH should likely focus on raising BP rather than HR as a fall in BP is the defining feature of this condition. Studies of the VSR have been performed in rats without identified vasovagal responses. Yakushin and colleagues applied linear acceleration in anesthetized rats and found increases in BP that were maximal during upward and forward translation \[36\]. HR was unaffected by single translations, but oscillations may influence it more gradually.

There are challenges in the study of various populations affected by syncope. The most common condition, vasovagal syncope may be difficult to objectively diagnose due to the intermittent nature of the symptoms. In particular, many patients have normal tilt testing in the laboratory setting and are only symptomatic during times of physical or emotional stress. A more easily diagnosed condition, postural orthostatic tachycardia syndrome, is far less common and patients frequently improve spontaneously after adolescence.

This study will focus on syncope caused by nOH because there is a larger population of potential subjects and laboratory testing is more reliable. It is our hypothesis that sinusoidal galvanic vestibular stimulation (sGVS) can be used to produce habituation of syncope in humans. sGVS has been used to activate muscle sympathetic nerve activity (MSNA) without side-effects beyond motion-sickness in a few test subjects. During habituation periods, subjects are able to read, listen to music, and watch TV, etc.

Eligibility Criteria:
Inclusion Criteria:

* Patient with unexpected intermittent syncope or a positive tilt test

Exclusion Criteria:

* Syncope cannot be related to significant heart disease
* cannot be not be related to serious medical illnesses that cause increased susceptibility to fainting, such as in Parkinson's Disease
* Pregnant or lactating women