Mapping autonomic, mood and cognitive effects of hypothalamic region deep brain stimulation

Abstract

Due to its involvement in a wide variety of cardiovascular, metabolic, and behavioral functions, the hypothalamus constitutes a potential target for neuromodulation in a number of treatment-refractory conditions. The precise neural substrates and circuitry subserving these responses, however, are poorly characterized to date. We sought to retrospectively explore the acute sequalae of hypothalamic region deep brain stimulation and characterize their neuroanatomical correlates. To this end we studied at multiple international centers 58 patients (mean age: 68.5 ± 7.9 years, 26 females) suffering from mild Alzheimer’s disease who underwent stimulation of the fornix region between 2007 and 2019. We catalogued the diverse spectrum of acutely induced clinical responses during electrical stimulation and interrogated their neural substrates using volume of tissue activated modelling, voxel-wise mapping, and supervised machine learning techniques. In total 627 acute clinical responses to stimulation – including tachycardia, hypertension, flushing, sweating, warmth, coldness, nausea, phosphenes, and fear – were recorded and catalogued across patients using standard descriptive methods. The most common manifestations during hypothalamic region stimulation were tachycardia (30.9%) and warmth (24.6%) followed by flushing (9.1%) and hypertension (6.9%). Voxel-wise mapping identified distinct, locally separable clusters for all sequelae that could be mapped to specific hypothalamic and extrahypothalamic gray- and white-matter structures. K-nearest neighbor classification further validated the clinico-anatomical correlates emphasizing the functional importance of identified neural substrates with area under the receiving operating characteristic curves (AUROC) between 0.67 – 0.91. Overall, we were able to localize acute effects of hypothalamic region stimulation to distinct tracts and nuclei within the hypothalamus and the wider diencephalon providing clinico-anatomical insights that may help to guide future neuromodulation work.

Diverging prefrontal cortex fiber connection routes to the subthalamic nucleus and the mesencephalic ventral tegmentum investigated with long range (normative) and short range (ex-vivo high resolution) 7T DTI

“…In the ICa’s ventral part, it is located lateral and most ventral even inferior to HDP fibers. The slMFB has an aslant and in larger parts trans-hypothalamic (Neudorfer et al 2021 ) course as previously described (Coenen et al 2011 , 2012 , 2018b ). This trans-hypothalamic route before bridging to the midbrain in the prerubral field (with formation of a VTA terminal field before continuing to other parts of the MVT) makes the analogy to the classically and in rodents described mfb complete.…”

“…?, the role of Dopamine (DA) in the region is not fully clear. slMFB superolateral branch of the medial forebrain bundle; VTA ventral tegmental area; PRF prerubral field (field H of Forel), hatched region in midbrain inset represents mesencephalic ventral tegmentum; ICa internal capsule anterior limb; ICp posterior limb; lh lateral hypothalamus; CP cerebral peduncle; OFC orbitofrontal cortex; STN subthalamic nucleus; HDP hyperdirect pathways; PFC prefrontal cortex; dlPFC dorsolateral; m medial; a anterior; d dosal; hip hippocampus in larger parts trans-hypothalamic (Neudorfer et al 2021) course as previously described (Coenen et al 2011(Coenen et al , 2012(Coenen et al , 2018b. This trans-hypothalamic route before bridging to the midbrain in the prerubral field (with formation of a VTA terminal field before continuing to other parts of the MVT) makes the analogy to the classically and in rodents described mfb complete.…”

Autonomic dysfunction after moderate-to-severe traumatic brain injury: symptom spectrum and clinical testing outcomes

“…Worse quality of life and psychological distress is reported in otherwise healthy patients with vasovagal syncope or POTS and neurological patients with concurrent autonomic dysfunction 26–28. Additionally, CAN regions are also important for cognition and emotional processing,29 30 which means that autonomic dysfunction may be an important biomarker for or contributor to post-TBI cognitive/psychological dysfunction. Furthermore, interoception, the ‘signalling and perception of internal bodily sensations’ is important for both cognitive and emotional function 31 32.…”

Autonomic dysfunction after moderate-severe traumatic brain injury: symptom spectrum and clinical testing outcomes

“…Additionally, there is significant overlap in regions of the brain important for autonomic function and those important in cognition and emotional processing, for example, hypothalamus, amygdala and anterior cingulate cortex 31,32 , which means that autonomic dysfunction may be an important biomarker for cognitive/psychological dysfunction.…”