In the United States, depression may currently be the leading disorder affecting children and young adults. Parasympathetic excess (PE) is associated with depression [1]. In general, the effect of PE is to slow or reduce most bodily functions (say, e.g., GI motility). It seems as if the net effect of slowing brain function is depression. This is supported by the fact that the anticholinergic properties of medications in the class of antidepressants also relieve PE. PE from the resting baseline tends to be associated with frank depression, including major depressive disorder (MDD), such as that which is associated with heart disease and other chronic diseases. Depression is associated with increased risk of mortality in patients with cardiovascular diseases (CVD, e.g., post-MI, coronary heart disease, CHF, CAD, unstable angina), whether CVD is primary or secondary due to chronic diseases other than heart disease (e.g., diabetes, COPD, Parkinson’s disease, etc.) [2–10]. PE from the Valsalva or PC challenges is also associated with depression [1]. Valsalva or PC PE often induces a secondary SE. The combination of PE with secondary SE is associated with depression with anxiety (e.g., bipolar disease or depression/anxiety cycles). PE with secondary SE is also associated with depression that is common in other syndromes, such as attention deficit syndromes (ADD or ADHD), fibromyalgia and other pain syndromes, chronic fatigue syndrome and other fatigue syndromes, post-traumatic stress disorder, hypertension with depression, labile hypertension [11, 12], palpitations, and unexplained arrhythmia or seizure [1].

Independent, simultaneous P&S monitoring is required to detect and document PE from the Valsalva or PC challenges and to detect and differentiate resting PE from normal. (With HRV alone, PE is not defined. More parasympathetic activity is normal. Normal parasympathetic activity and PE are not differentiated by HRV alone.) In fact too much parasympathetic activity looks “very” normal. See Fig. 16.1. Most agents used to treat depression have direct or indirect anticholinergic effects, e.g., tricyclic antidepressants, selective norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), anxiolytics, antipsychotics, and benzodiazepines. These agents may reduce parasympathetic activity and relieve PE. From an autonomic perspective, the SSRIs tend to have a weak effect on the PSNS [personal communication]. Since they affect the serotonergic system, they have an indirect cholinergic effect. As a result, while they tend to help manage symptoms, they seem to have the weakest effect on the PSNS of the three classes of agents. For example, after 3 months of SSRI therapy, often there is no significant change in PE.

PE with depression, without cardiovascular disease, may be treated with anticholinergic medications, titrated against establishing and maintaining normal (resting) P&S balance. For PE with depression, with cardiovascular disease, there are several therapy options depending on patient history. SE may present with (and cause) cardiovascular disease. In more advanced forms of autonomic dysfunction, SE may be masked, but manifest as high BP or high HR. For all of these cases and for geriatric patients (for whom low-normal SB is recommended), the recommendation would be to switch to, or titrate, carvedilol, history dependent, against establishing and maintaining low-normal SB (0.4< SB <1.0). If carvedilol is not tolerated, a combination of a beta-blocker with an anticholinergic would be recommended [1]. (Prior to carvedilol, the recommendation was a beta-blocker with an anticholinergic, history dependent. Carvedilol is simply a “convenience” to facilitate compliance and minimize cost.) A last possibility is that as a result of the CVD (including hypertension), the sympathetic blockade (e.g., beta-blockers or antihypertensives) itself may induce PE (measured as abnormally low SB) by inducing sympathetic insufficiency. In these cases, assuming the patient’s BP or HR are well controlled, or low, consider titrating lower the sympathetic blockade, history dependent, to establish and maintain low-normal SB and relieve the (relative) resting PE. If the patient’s BP or HR is not well controlled, then consider an anticholinergic to relieve the PE.

A significant portion of depressed patients, who are prescribed agents that relieve PE, are also relieved of the depression. Further, especially in younger patients, once the PE is relieved, patients tend to be able to be weaned from the anticholinergic and are able to carry forward, without medication, until some other clinical events.

Studies have shown that pacing in bradycardia patients improves different aspects of cognitive performance, such as memory function, mental acuity, visual learning, verbal intelligence or dementia, and sensorimotor functions [13–15]. There is a significant relationship between cognitive impairment and the cerebral blood flow and blood volume in patients with dementia [16]. Since HR is an important factor in the regulation of cerebral circulation [14, 17], the importance of cardiac parameters in the preservation or restoration of cognitive functions (especially in the elderly) is increasingly acknowledged.

Several studies have demonstrated the superiority of closed-loop stimulation (CLS) to conventional sensors regarding the HR increase during mental efforts [17–21]. But no study investigated if this translates into improved cognitive performance in either short or long term. CLS provides the appropriate and individually tailored HR adaptation during physical exercise [18, 19, 21, 22]. Furthermore, it has been reported that CLS is associated with a lower atrial tachyarrhythmia burden than an overdrive pacing algorithm or accelerometer-based rate adaptive pacing at 7 months after pacemaker implantation [23]. In addition, a significant improvement in New York Heart Association (NYHA) class and the left ventricular ejection fraction after, on average, 18.5 months of CLS was observed in pacemaker patients with CHF and preimplantation ejection fraction of <40 % [24]. Several groups demonstrated sensitivity of CLS to various conditions of daily life, including handgrip, arm waving, picking up an object, standing, posture change, and Valsalva maneuver, which was attributed to the ability of the implanted device to track the sympathetic modulation to the heart [18, 20, 25]. On the other hand, few patients reported discomfort during the night due to fast HRs driven by CLS [19]. In a study of 131 chronotropically incompetent patients, twice as many patients preferred CLS over accelerometer-based pacing [21].

While accelerometer (alone or in combination with minute ventilation sensor) was shown to be ineffective in improving the functional status or quality of life in comparison with dual-chamber pacing alone [26], the therapeutic potential of CLS has not been fully explored. The observed published differences do not amass for a conclusion if chronotropically incompetent patients are generally better treated if receiving a pacemaker sensor that measures a parameter directly related to the sympathetic state than an accelerometer sensor. The COGNITION study aims at long-term comparison of two rate-adaptive systems, focusing on the cognitive performance, patient self-assessment, quality of life, and the incidence of atrial fibrillation [27].