Hypothalamic Deep Brain Stimulation Influences Autonomic and Limbic Circuitry Involved in the Regulation of Aggression and Cardiocerebrovascular Control in the Göttingen Minipig

Abstract

Background: Deep brain stimulation (DBS) in the ventral tuberal hypothalamus (VTH) is currently under investigation for the treatment of severe obesity. Stimulation impact on a number of closely related hypothalamic neural systems could potentially influence normal hypothalamic function and thereby generate adverse side effects. Objective: To assess the feasibility and safety of VTH DBS in a non-primate large animal model. Methods: In the VTH of 6 Göttingen minipigs, quadropolar leads were implanted bilaterally (n = 2) or unilaterally (n = 4), using optimized MRI sequences allowing identification of major diencephalic landmarks. Heart rate, weight, behavior and nighttime locomotor activity were recorded throughout the study period. Two of the unilaterally implanted minipigs were examined with [¹⁵O]H₂O positron emission tomography (PET) scans performed in DBS-off and DBS-on mode. Results: VTH DBS elicited an amplitude-dependent increase in heart rate and transient aggressive behavior. PET demonstrated that VTH DBS caused a global increase in cerebral blood flow velocities and decreased mean transit time. Conclusions: VTH DBS results in behavioral and physiological changes, which may derive from activation of closely related limbic and autonomic networks. Caution and further studies of longer length should be requested before this procedure is used more widely in humans.

Critical review evaluating the pig as a model for human nutritional physiology

“…Recent development suggests that the deep-brain stimulation (DBS), a procedure for the treatment of Parkinson's or Nutrition Research Reviews depression, might also be used to combat obesity (262)(263)(264)(265) . Hypothalamic DBS was validated in the Göttingen minipig (267,268) and resulted in reduced weight gain (269) , as well as in behavioural and physiological changes that could be related to the activation of limbic and autonomic brain networks (270) . Hypothalamic DBS was validated in the Göttingen minipig (267,268) and resulted in reduced weight gain (269) , as well as in behavioural and physiological changes that could be related to the activation of limbic and autonomic brain networks (270) .…”

Decoding Ventromedial Hypothalamic Neural Activity during Male Mouse Aggression

“…This architecture could potentially support recurrent excitation to maintain or amplify a sensory signal from afferent inputs (Millhouse, 1973;Nishizuka and Pfaff, 1989;Canteras et al, 1994). Neurons in the VMHvl also express a variety of neuromodulator receptors, including serotonin 1A, 2A, and 2C, muscarinic acetylcholine, and oxytocin receptors (Freund-Mercier et al, 1987;Levey, 1993;Zhang et al, 1999;Huang et al, 2004). Because many neuromodulators, such as serotonin and dopamine, change their levels dynamically during the course of aggressive behaviors, they may potentiate VMHvl cell excitability under conditions of high aggressive arousal state or during the post-male stimulus period.…”

“…Early experiments performed on cats during the 1920s, which severed the hypothalamus from midbrain and brainstem structures, first demonstrated that the intact hypothalamus is necessary for the expression of rage (Bard, 1928). Later, a series of classic electric stimulation experiments showed that complex aggressive actions could be evoked by stimulating the hypothalamus in a variety of species (Putkonen, 1966;Lipp and Hunsperger, 1978;Kruk et al, 1983;Siegel and Pott, 1988;Ettrup et al, 2012). In particular, Kruk et al (1983) mapped out a distributed "hypothalamic attack area" in rats by comparing the effects of hundreds of electrode stimulation sites.…”

Sex differences in mania phenotype and ethanol consumption in the lateral hypothalamic kindled rat model

“…Further evidence emerges from neurosurgical case reports of hypothalamic hamartomata where patients with these rare non-neoplastic nodules present with manic-like symptoms described as mood instability, aggressiveness, restlessness and severe rage attacks accompanied by a strange feeling of ‘pressure to laugh' called gelastic seizures. 33,34 On the other hand, preclinical studies in rats, 35 pigs 36 and monkeys 37 have shown that high frequency stimulation of the hypothalamus engages functional circuits involved in different behaviors reminiscent of mania such as hypersexuality, aggression, increased locomotor activity and disturbed sleep–wake cycle. 38 However, we have specifically employed the kindling paradigm to facilitate spontaneous firing of the lateral hypothalamic neurons and hence induce manic-like behaviors that can carry over during the poststimulation phase of the experiment.…”