Neurosurg Focus. 2017 Sep;43(3):E15. doi: 10.3171/2017.6.FOCUS17256.

The hypothalamus at the crossroads of psychopathology and neurosurgery.

Barbosa DAN1,2, de Oliveira-Souza R1,3, Monte Santo F1,4, de Oliveira Faria AC1,3, Gorgulho AA5,6, De Salles AAF5,6.

1 Department of Clinical Neuroscience, D’Or Institute for Research and Education.
2 Division of Neurosurgery and.
3 Department of Neurology and Psychiatry, Gaffrée e Guinle University Hospital, Federal University of the State of Rio de Janeiro.
4 Intensive Care Unit, Icaraí Hospital, Niteroi, RJ.
5 HCor Neuroscience, São Paulo, Brazil; and.
6 Department of Neurosurgery and Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, California.



The neurosurgical endeavor to treat psychiatric patients may have been part of human history since its beginning. The modern era of psychosurgery can be traced to the heroic attempts of Gottlieb Burckhardt and Egas Moniz to alleviate mental symptoms through the ablation of restricted areas of the frontal lobes in patients with disabling psychiatric illnesses. Thanks to the adaptation of the stereotactic frame to human patients, the ablation of large volumes of brain tissue has been practically abandoned in favor of controlled interventions with discrete targets. Consonant with the role of the hypothalamus in the mediation of the most fundamental approach-avoidance behaviors, some hypothalamic nuclei and regions, in particular, have been selected as targets for the treatment of aggressiveness (posterior hypothalamus), pathological obesity (lateral or ventromedial nuclei), sexual deviations (ventromedial nucleus), and drug dependence (ventromedial nucleus). Some recent improvements in outcomes may have been due to the use of stereotactically guided deep brain stimulation and the change of therapeutic focus from categorical diagnoses (such as schizophrenia) to dimensional symptoms (such as aggressiveness), which are nonspecific in terms of formal diagnosis. However, agreement has never been reached on 2 related issues: 1) the choice of target, based on individual diagnoses; and 2) reliable prediction of outcomes related to individual targets. Despite the lingering controversies on such critical aspects, the experience of the past decades should pave the way for advances in the field. The current failure of pharmacological treatments in a considerable proportion of patients with chronic disabling mental disorders is reminiscent of the state of affairs that prevailed in the years before the early psychosurgical attempts. This article reviews the functional organization of the hypothalamus, the effects of ablation and stimulation of discrete hypothalamic regions, and the stereotactic targets that have most often been used in the treatment of psychopathological and behavioral symptoms; finally, the implications of current and past experience are presented from the perspective of how this fund of knowledge may usefully contribute to the future of hypothalamic psychosurgery.




Psychosurgery, or the neurosurgical approach to the treatment of the mind and behavior, has been part of the evolution of human civilizations1,23 and it gained popularity between the early lobotomies and the adaptation of the stereotactic apparatus for operations on the human brain.13,28 The development of psychoactive drugs by the end of the 1950s and the fierce attacks that psychiatry suffered in the 1970s by the antipsychiatric movement eventually cornered psychosurgery in a conceptual and ethical trap which led to a sharp decline in the rate of psychosurgical interventions. Thus, by the end of the 1970s, psychosurgery was performed in only a few centers in the world.29 However, owing to the increasing recognition of the limits of psychopharmacology, the initial enthusiasm that followed the introduction of psychoactive drugs also underwent a sharp decline in the 1990s. The blunt fact is that countless individuals with severe mental illness are still condemned to be kept away from society due to a lack of treatment for their conditions.31 This reality has provided momentum for the application of modern and consolidated neuromodulation techniques to the treatment of these hopeless patients. The need to find new solutions that mitigate this enormous human suffering worldwide has been a major incentive for the revival of psychosurgery that is currently underway. It has become imperative to address structures and functional systems lying at the crossroads of psychopathology and neurosurgery to improve old treatments and develop new ones.

Throughout the tortuous history of psychosurgery, a handful of neurosurgical approaches were developed for several conditions.3,5 The hypothalamus has commonly been used as a stereotactic target due to its key role in the regulation of fundamental approach-avoidance behaviors.3 Targeting the hypothalamus is at once challenging and promising, largely because of the dense organization of its nuclei and pathways.15,20 In the parasagittal plane, the hypothalamus has 3 major rostrocaudal regions, namely, the preoptic (or chiasmal), the tuberal (or infundibular), and the mammillary. This division is supplemented by a tripartite mediolateral division in periventricular, nuclear, and lateral zones, each with a distinct cellular architecture and hodology.14-16,20  The periventricular zone is rudimentary in humans, consisting of neurons without a clear structural organization, but important for mood regulation and body homeostasis.24 The nuclear zone contains the hypothalamic nuclei, which are functionally associated, from rostral to caudal, with thermal regulation and endocrine regulation of sexual behavior (preoptic n.), antidiuretic hormone and oxytocin secretion, neuroendocrine-autonomic integration (paraventricular n.), regulation of circadian rhythms (suprachiasmatic n.), secretion of neurohypophyseal hormones (supraoptic n.), food intake, cardiovascular regulation, monitoring of adipose tissue fat (arcuate n.), daytime feeding, emotional responses to stress/panic, libido (dorsomedial n.), food intake, weight gain/loss, lipolysis, sexual behavior (ventromedial n.), sympathetic responses, defensive and aggressive behaviors (dorsal or posterior n.), sleep-wakeful rhythms; motivated behaviors in relation to food, water, sex, and drugs (tuberomammillary n.), and episodic memory (mammillary n.).3,20,24,32 The lateral region is an associative zone, through which run a number of fibers that connect the local nuclei with rostral and caudal regions of the forebrain and brainstem. The chief fiber systems are the medial forebrain bundle, the fornix, the stria terminalis, the mammillo-thalamic tract, and the ansa peduncularis.22,33

Notwithstanding several technical limitations, stereotactic approaches to the hypothalamus have yielded encouraging results in animal studies performed in the 1940s and the 1950s.32 Thereafter, the hypothalamus and its divisions were explored and used in the treatment of aggressiveness (posterior hypothalamus), morbid obesity (lateral or ventromedial nuclei), sexual deviations (ventromedial nucleus), and drug dependence (ventromedial nucleus) from the mid-1960s to the late 1970s, with results ranging from poor to satisfactory to excellent.3,9,19,22,25 At the time, neurosurgical procedures for psychiatric diseases lacked a solid theoretical basis and were performed in patients with poorly described clinical presentations, dubious diagnostic criteria and uncertain surgical indications, therefore leaving an open flank for ethical criticisms and public backlash.26

More recently, deep brain stimulation (DBS) emerged as a safe, reversible, and ethically acceptable technique to modulate specific brain regions. Hypothalamic DBS for psychiatric symptoms is mostly used for refractory (i.e., drug-unresponsive) aggressive behavior (targeting the posteromedial hypothalamus) in mentally impaired patients, while other potential applications have been investigated on clinical grounds, such as morbid obesity.3,6,8,17,34 Incidental behavioral changes elicited during the implantation of DBS electrodes in the hypothalamus may provide insights towards novel neurosurgical treatments for psychiatric symptoms. The first example is the case of a patient successfully treated with DBS for Parkinson’s disease who presented acute transient aggressive behavior during intraoperative electrical stimulation of the exploratory medial track, at the border of the posteromedial hypothalamus.4 This paved the way for the rebirth of hypothalamic psychosurgery.8 Hamani et al. presented a case of ventral hypothalamic DBS for morbid obesity with side effects related to memory due to accidental fornix stimulation, which began to be investigated as an therapeutic option for Alzheimer’s disease.11,17 This represent the need for further developments in stereotactic targeting in the hypothalamus. Further analyses of single cases reporting on the serendipitous effects of electrical stimulation, such as a panic attack, is mandatory since they may streamline the search for new targets for these symptoms.34

The implications of combining stereotactic hypothalamic psychosurgery with novel brain imaging and modulatory techniques are potentially immense.5,7,21,27,30 The current neuroimaging modalities, such as  tractography and resting-state fMRI, have made it possible to investigate the minutiae of the structural and functional connectivity of target regions in the hypothalamus.15,16 This can be coupled with modern neurosurgical targeting paradigms (e.g. closed-loop, directional DBS, radiosurgery) to optimize neuromodulation according to specific neural networks. Furthermore, the newest neuromodulation approaches, such as laser ablation, focused ultrasound, optogenetic stimulation, are on the verge of being added to the therapeutic arsenal of hypothalamic psychosurgery.2,18 The systematization of the reports of stereotactic surgery targeting the hypothalamus should provide the foundations for these promising interventions.

We can envision a future where the hypothalamus and its connections may be widely targeted in the treatment of symptoms as heterogeneous as aggressiveness, morbid obesity, substance abuse, panic attacks, memory impairment, and paraphilic disorders.3,9,10,12 A handful of possibilities are already under investigation in tertiary clinical settings.6,8,11,17 This article features the MR images from a patient with DBS electrodes implanted in the ventromedial hypothalamus, which hints our following publication, the BLESS Study Protocol, a registered trial on low-frequency VMH DBS for morbid obesity.6 Results of this trial are expected to be published later this year.



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