Neurogenic Orthostatic Hypotension patients show reduced brainstem connectivity

[pattismith]

Reduced brainstem functional connectivity in patients with peripheral autonomic failure

Jacquie Bakerab Kurt Kimpinskiac

School of Kinesiology, Western University, London, Ontario, Canada
Department of Clinical Neurological Sciences, University Hospital, London Health Sciences Centre, London, Ontario, Canadac
Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
Received 12 April 2019, Revised 31 May 2019, Accepted 30 June 2019,
Available online 2 July 2019.

Highlights

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NOH patients show reduced brainstem connectivity at rest and during Valsalva.
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Brainstem connectivity was reduced to central autonomic network structures.
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Brainstem-cerebellum connectivity was negatively correlated with autonomic function.

Abstract
Autonomic homeostasis is dependent upon several brainstem nuclei, as well as several cortical and subcortical structures.
Together, these sites make up, in part, the central autonomic network.

Neurogenic orthostatic hypotension (NOH) is a cardinal feature of autonomic failure that occurs due to a failure to increase sympathetic efferent activity in response to postural changes.

Therefore, the purpose of the current study was to investigate brainstem functional connectivity in NOH patients with peripheral autonomic lesions resulting in autonomic failure.

Fifteen controls (63 ± 13 years) and fifteen Neurogenic Orthostatic Hypotension patients (67 ± 6 years; p = .2) with peripheral autonomic dysfunction completed 5-min of rest and three Valsalva maneuvers during a functional brain scan.

Functional connectivity from the brainstem to cortical and subcortical structures were contrasted between patients and controls.

At rest controls had significantly greater brainstem connectivity to the anterior cingulate cortex (T-value: 4.29), left anterior insula (T-value:3.31), left putamen (T-value:3.31) and bilateral thalamus (TRIGHT-value: 3.83; TLEFT-value:4.25) (p-FDR < 0.005).

During Valsalva, controls showed significantly more connectivity between the brainstem and both the left anterior (cerebellum 4/5) and bilateral posterior cerebellum (cerebellar 9 and left cerebellar 6).

Other cerebellar regions included brainstem-to-vermis.
Other brainstem-to-cortical and subcortical regions included: bilateral putamen, posterior cingulate cortex (PCC), amygdala and medial prefrontal cortex.

There was a significant negative correlation between the brainstem-cerebellar connectivity and severity of autonomic dysfunction (p < .01). During recovery phase of the Valsalva, controls had greater brainstem connectivity to the left thalamus (T-value:4.17); PCC (T-value:3.32); right putamen (T-value:3.28); right paracingulate gyrus (T-value:3.25) and left posterior cerebellum (C9) (T-value:3.21) (p-FDR < 0.05).

The effect sizes for each brainstem connectivity during Valsalva and recovery ranged from moderate to strong.

Patients with autonomic failure show reduced coupling between the brainstem and regions of the central autonomic network, including the cerebellum, insula, thalamus and cingulate cortices.

Connectivity was associated with autonomic impairment. These findings may suggest impaired brainstem connectivity in patients with autonomic failure.

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[Sidny]

Wouldn’t be surprised if ME patients, fibro patients and others with “idiopathic” nuero issues show reduced brain stem connectivity. Seems like a relatively simple test that should be implemented more widely.

I wonder what the causes could be? (stroke, viral brain infection, CCI? perhaps)
Any treatment ideas?

Seems like a lot of ME patients would meet the criteria for an NOH diagnosis.

In contrast, a diagnosis of idiopathic NOH was given if, again, there was evidence of orthostatic hypotension, along with gastrointestinal issues or other questionable phenomenon such as olfactory impairment, but not meeting criteria for other alpha-synucleinopathies

In the current study, patients had significantly less brainstem connectivity to key autonomic structures including the cerebellum, thalamus, cingulate cortices, medial prefrontal and insula. These regions have all been highly implicated in autonomic regulation both in animals and humans, and in health and disease

4.1. Clinical implications

The following findings may provide insight into differential susceptibility to patient fall risk, increased morbidity and/or more severe autonomic dysfunction. This hypothesis is congruent with the results of Zhou et al., (2012) who applied functional connectivity in healthy controls to provide new insights into how the brain's functional connectivity may predict vulnerability to neurodegenerative disease (Zhou et al., 2012).

5. Conclusion

In the current study, patients with peripheral autonomic failure had significantly less functional connectivity between the brainstem and key cortical autonomic structures both at rest and during an autonomic maneuver. Patients showed reduced coupling between brainstem and regions of the central autonomic network, including the cerebellum, insula, thalamus and cingulate cortices. These results may be attributed to two mechanistic models, including nodal stress and transneuronal spread, which may contribute, in part, to the pathophysiology of autonomic failure.

 

[pattismith]

studies on brainstem connectivity seem a new research area.

I found two other field were brainstem connectivity was studied: Temporal Epilepsy (impaired connectivity) and chronic pain (increased connectivity)



Brainstem Pain-Control Circuitry Connectivity in Chronic Neuropathic Pain

Emily P. Mills, Flavia Di Pietro, Zeynab Alshelh, Chris C. Peck, Greg M. Murray, E. Russell Vickers and Luke A. Henderson

Journal of Neuroscience 10 January 2018, (ful text free)

Abstract
Preclinical investigations have suggested that altered functioning of brainstem pain-modulation circuits may be crucial for the maintenance of some chronic pain conditions.

While some human psychophysical studies show that patients with chronic pain display altered pain-modulation efficacy, it remains unknown whether brainstem pain-modulation circuits are altered in individuals with chronic pain.
The aim of the present investigation was to determine whether, in humans, chronic pain following nerve injury is associated with altered ongoing functioning of the brainstem descending modulation systems.

Using resting-state functional magnetic resonance imaging, we found that male and female patients with chronic neuropathic orofacial pain show increased functional connectivity between the rostral ventromedial medulla (RVM) and other brainstem pain-modulatory regions, including the ventrolateral periaqueductal gray (vlPAG) and locus ceruleus (LC).

We also identified an increase in RVM functional connectivity with the region that receives orofacial nociceptor afferents, the spinal trigeminal nucleus. In addition, the vlPAG and LC displayed increased functional connectivity strengths with higher brain regions, including the hippocampus, nucleus accumbens, and anterior cingulate cortex, in individuals with chronic pain. These data reveal that chronic pain is associated with altered ongoing functioning within the endogenous pain-modulation network. These changes may underlie enhanced descending facilitation of processing at the primary synapse, resulting in increased nociceptive transmission to higher brain centers. Further, our findings show that higher brain regions interact with the brainstem modulation system differently in chronic pain, possibly reflecting top–down engagement of the circuitry alongside altered reward processing in pain conditions.

Brainstem Functional Connectivity Disturbances in Epilepsy may Recover After Successful Surgery.
González HFJ1,2, Goodale SE1,2,3, Jacobs ML4,5, Haas KF5, Landman BA2,6,7,8, Morgan VL1,2,3,5,6,8, Englot DJ1,2,3,8.
2019

Abstract
BACKGROUND:
Focal seizures in temporal lobe epilepsy (TLE) are associated with widespread brain network perturbations and neurocognitive problems.
OBJECTIVE:
To determine whether brainstem connectivity disturbances improve with successful epilepsy surgery, as recent work has demonstrated decreased brainstem connectivity in TLE that is related to disease severity and neurocognitive profile.
METHODS:
We evaluated 15 adult TLE patients before and after (>1 yr; mean, 3.4 yr) surgery, and 15 matched control subjects using magnetic resonance imaging to measure functional and structural connectivity of ascending reticular activating system (ARAS) structures, including cuneiform/subcuneiform nuclei (CSC), pedunculopontine nucleus (PPN), and ventral tegmental area (VTA).
RESULTS:
TLE patients who achieved long-term postoperative seizure freedom (10 of 15) demonstrated increases in functional connectivity between ARAS structures and fronto-parietal-insular neocortex compared to preoperative baseline (P = .01, Kruskal-Wallis), with postoperative connectivity patterns resembling controls' connectivity. No functional connectivity changes were detected in 5 patients with persistent seizures after surgery (P = .9, Kruskal-Wallis). Among seizure-free postoperative patients, larger increases in CSC, PPN, and VTA functional connectivity were observed in individuals with more frequent seizures before surgery (P < .05 for each, Spearman's rho). Larger postoperative increases in PPN functional connectivity were seen in patients with lower baseline verbal IQ (P = .03, Spearman's rho) or verbal memory (P = .04, Mann-Whitney U). No changes in ARAS structural connectivity were detected after successful surgery.
CONCLUSION:
ARAS functional connectivity disturbances are present in TLE but may recover after successful epilepsy surgery. Larger increases in postoperative connectivity may be seen in individuals with more severe disease at baseline.