Jacquie Baker

Forebrain organization for autonomic cardiovascular control

This brief review discusses the current state of knowledge regarding the cortical circuitry associated with autonomic cardiovascular responses to volitional exercise in conscious humans. Studies to date have emphasized the autonomic nervous system adjustments that occur through top-down central command features as well as bottom-up signals arising from skeletal muscle. While in its infancy, the pattern of cortical circuitry associated with exercise seem to depend on the nature of the exercise but with common patterns arising in the insula cortex, dorsal anterior cingulate cortex, medial prefrontal cortex, and hippocampus.

Effect of age on the hemodynamic and sympathetic responses at the onset of isometric handgrip exercise

Cardiac and peripheral vasomotor factors contribute to the rapid pressor response at the onset of isometric handgrip exercise. We tested the hypothesis that age enhances the sympathetic and vasoconstrictor response at the onset of isometric handgrip exercise so that the pressor response is maintained, despite a diminished cardiac function. Twelve young and twelve older (24 ± 3 and 63 ± 8 yr) individuals performed 20-s isometric handgrip exercise at 30, 40, or 50% of maximal voluntary contraction force. Muscle sympathetic nerve activity (MSNA) was measured using microneurography. Mean arterial pressure (MAP) and cardiac output (Q) were assessed continuously by finger plethysmography and total peripheral resistance was calculated. MAP increased with the onset of handgrip; this increase was associated with handgrip intensity and was similar in both groups. Heart rate and Q increased with increasing handgrip intensity in both groups, but increases were greater in young vs. older individuals (age × handgrip intensity interaction, P < 0.05). MSNA burst frequency increased (P < 0.01), while MSNA burst incidence tended to increase (P = 0.06) with increasing handgrip intensity in both groups. The change in MSNA between baseline and handgrip, for both frequency and incidence, increased with increasing handgrip intensity for both groups. There was no effect of handgrip intensity or age on total peripheral resistance. The smaller heart rate and Q response during the first 20 s of handgrip exercise in older individuals was not accompanied by a greater sympathetic activation or vasoconstrictor response. However, increases in MAP were similar between groups, indicating that the pressor response at the onset of handgrip exercise is preserved with aging.

Management of Supine Hypertension Complicating Neurogenic Orthostatic Hypotension

Neurogenic orthostatic hypotension (NOH) can be present in a number of disorders, including synucleinopathies, autoimmune disorders, and various genetic disorders. All are characterized by defective norepinephrine release from sympathetic terminals upon standing, resulting in impaired vasoconstriction. NOH is defined as a drop in systolic blood pressure ≥20 mmHg or diastolic blood pressure ≥10 mmHg, or both, within 3 minutes of standing or head up-tilt at a minimum of 60°. However, approximately 50% of patients have associated supine hypertension, which greatly complicates treatment. Supine hypertension not only is a common side effect of many anti-hypotensive agents but is also present in untreated patients, suggesting it is, in part, innate to the pathophysiology of autonomic dysfunction. Pathological mechanisms differ depending on the underlying autonomic disorder. In central neurodegenerative disorders, residual post-ganglionic sympathetic activity is likely the primary mechanism, whereas plasma angiotensin, aldosterone, and inappropriate mineralocorticoid receptor activity may contribute in peripheral autonomic lesions. Baroreflex failure/loss of baroreflex buffering is common to both. More work is required. Clinically, there is much dispute regarding the treatment of supine hypertension when there is a risk of exacerbating orthostatic hypotension. However, given the similar levels of end-organ damage (i.e., heart attack and stroke) seen with transient hypertension, it seems clear that treatment is important. Current therapies for both NOH and supine hypertension include a combination of pharmacological and conservative measures. However, in addition to the current standard of care, protocols may consider 24-h blood pressure monitoring and potential future examination of the peripheral post-ganglionic sympathetic nerves in order to apply individualized adjunct therapies. Finally, no anti-hypertensive agents are currently approved for use in this patient population, and development of novel therapies should focus on short-acting agents, selective to the supine position, that act primarily at night when hypertension is most severe/prolonged.

Impaired cortical autonomic responses during sympathetic activation in Neurogenic Orthostatic Hypotension characterized by post-ganglionic autonomic dysfunction

PURPOSE Neurogenic orthostatic hypotension (NOH), is a cardinal feature of autonomic dysfunction. The cortical autonomic network (CAN) is a network of brain regions associated with autonomic function. Therefore, our objective was to investigate whether impairment of CAN structures is involved in the pathophysiology of NOH. METHODS Fifteen controls (63±13 years) and fifteen NOH patients (67±6 years; p=0.2) with peripheral autonomic dysfunction completed standard tests of parasympathetic [Deep Breathing (DB)] and sympathetic [Valsalva maneuver (VM)] activation during a functional MRI. Blood-oxygen level dependent (BOLD) contrasts were obtained and contrasted. RESULTS Hemodynamics: Compared to controls, patients had significantly smaller heart rate responses to DB (C:15.23±9.6 vs. NOH: 5.7±2.1) and Valsalva ratios (C:2.1±0.47 vs. NOH: 1.2±0.1; p<0.001). NOH patients had absent adrenergic phases (late phase II and phase IV) during VM as per a qualitative analysis. BOLD: During VM, controls had greater activation in the right hippocampus (T-value: 8.03), left posterior cingulate (TL:7.6) and bilateral thalamus (TR:7.41, TL:8.45; p<0.05). During phase IV, controls had greater activation in the right hippocampus (TR:5.78l p<0.05). Following subtraction analysis, no significant differences were evident during DB. CONCLUSION NOH patients have significantly less CAN activation during sympathetic, but not parasympathetic, activation. Impaired cortical autonomic networks associated with sympathetic activation may be involved in the pathophysiology of NOH.Neurogenic orthostatic hypotension (NOH) is a cardinal feature of autonomic dysfunction. The cortical autonomic network (CAN) is a network of brain regions associated with autonomic function. Therefore, our objective was to investigate whether impairment of CAN structures is involved in the pathophysiology of NOH. Fifteen controls (63 ± 13 yr) and 15 NOH patients (67 ± 6 yr; P = 0.2) with peripheral autonomic dysfunction completed standard tests of parasympathetic [deep breathing (DB)] and sympathetic [Valsalva maneuver (VM)] activation during a functional MRI. Blood-oxygen-level dependent (BOLD) contrasts were obtained and contrasted. Compared with controls, patients had significantly smaller heart rate responses to DB (control: 15.23 ± 9.6 vs. NOH: 5.7 ± 2.1) and Valsalva ratios (control: 2.1 ± 0.47 vs. NOH: 1.2 ± 0.1; P < 0.001). NOH patients had absent adrenergic phases (late phase II and phase IV) during VM as per a qualitative analysis. During VM, controls had greater activation in the right hippocampus (T-value: 8.03), left posterior cingulate (TL: 7.6), and bilateral thalamus (TR: 7.41, TL: 8.45; P < 0.05). During phase IV, controls had greater activation in the right hippocampus (TR: 5.78l P < 0.05). Following subtraction analysis, no significant differences were evident during DB. In conclusion, NOH patients have significantly less CAN activation during sympathetic, but not parasympathetic, activation. Impaired CANs associated with sympathetic activation may be involved in the pathophysiology of NOH. NEW & NOTEWORTHY Neurogenic orthostatic hypotension (NOH) is a cardinal feature of autonomic dysfunction characterized by failure of reflexive sympathetic activation. Our result reveal that patients with autonomic dysfunction caused by postganglionic sympathetic impairment also have impaired activation of structures within the cortical autonomic network. Impaired activation is evident during a test of sympathetic, but not parasympathetic, activation. Impaired cortical autonomic networks associated with sympathetic activation may be involved in the pathophysiology of NOH.

Cerebellar impairment during an orthostatic challenge in patients with neurogenic orthostatic hypotension

OBJECTIVE Compare activation patterns within the cortical autonomic network in patients with neurogenic orthostatic hypotension (NOH) versus healthy age-matched controls during an orthostatic challenge. METHODS Fifteen health controls and 15 NOH patients performed 3 Valsalva maneuvers, and 5-min of lower-body negative pressure (LBNP) during a functional brain MRI. RESULTS Compared to controls, NOH patients had significantly less activation within the cerebellum during both LBNP and VM. Both groups had significant activation of the bilateral insula and left thalamus during LBNP. No significant differences were found during the recovery phase of LBNP. CONCLUSIONS The cerebellum, which plays an important role in vestibulo-sympathetic reflexes, important for blood pressure adjustments during postural changes, appear to be affected in patients with NOH. The cerebellum also appears to be affected during other baroreflex mediated stressors such as the VM. SIGNIFICANCE Orthostatic reflexes mediated by the cerebellum may be impaired in patients with NOH. The results suggest an additional pathological pathway in patients with autonomic failure.