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Complex negative emotions induced by electrical stimulation of the human hypothalamus

Open AccessPublished:April 08, 2022DOI:https://doi.org/10.1016/j.brs.2022.04.008

      Highlights

      • We studied a patient with 170 electrodes in the brain including the hypothalamus.
      • Hypothalamic stimulation caused profound change in subject's affective state.
      • Confirmed findings with dose effect and sham stimulations.
      • Mapped propagation of signals from the hypothalamic site to other brain sites.
      • Propagation of electrical current correlated with measures of resting connectivity.

      Abstract

      Background

      Stimulation of the ventromedial hypothalamic region in animals has been reported to cause attack behavior labeled as sham-rage without offering information about the internal affective state of the animal being stimulated.

      Objective

      To examine the causal effect of electrical stimulation near the ventromedial region of the human hypothalamus on the human subjective experience and map the electrophysiological connectivity of the hypothalamus with other brain regions.

      Methods

      We examined a patient (Subject S20_150) with intracranial electrodes implanted across 170 brain regions, including the hypothalamus. We combined direct electrical stimulation with tractography, cortico-cortical evoked potentials (CCEP), and functional connectivity using resting state intracranial electroencephalography (EEG).

      Results

      Recordings in the hypothalamus did not reveal any epileptic abnormalities. Electrical stimulations near the ventromedial hypothalamus induced profound shame, sadness, and fear but not rage or anger. When repeated single-pulse stimulations were delivered to the hypothalamus, significant responses were evoked in the amygdala, hippocampus, ventromedial-prefrontal and orbitofrontal cortices, anterior cingulate, as well as ventral-anterior and dorsal-posterior insula. The time to first peak of these evoked responses varied and earliest propagations correlated best with the measures of resting-state EEG connectivity and structural connectivity.

      Conclusion

      This patient's case offers details about the affective state induced by the stimulation of the human hypothalamus and provides causal evidence relevant to current theories of emotion. The complexity of affective state induced by the stimulation of the hypothalamus and the profile of hypothalamic electrophysiological connectivity suggest that the hypothalamus and its connected structures ought to be seen as causally important for human affective experience.

      Keywords

      1. Introduction

      Electrical stimulation of the hypothalamus in non-human mammals causes affective responses including hissing, growling, piloerection, pupillary dilation, and even attack behavior [
      • Hess W.R.
      • Akert K.
      Experimental data on role of hypothalamus in mechanism of emotional behavior.
      ]. Modern neuroscience research using optogenetics has uncovered specific subtypes of hypothalamic neurons within the ventromedial nucleus to be causally linked to such behavioral phenotypes [
      • Anderson D.J.
      Optogenetics, sex, and violence in the brain: implications for psychiatry.
      ]. While great progress has been made in mapping the mechanisms underlying animals’ affective defensive behavior, animals cannot report their internal emotional state while being stimulated. As such, the affective states caused by the stimulation of the human hypothalamus remains to be determined [
      • Barbosa D.A.N.
      • de Oliveira-Souza R.
      • Monte Santo F.
      • de Oliveira Faria A.C.
      • Gorgulho A.A.
      • De Salles A.A.F.
      The hypothalamus at the crossroads of psychopathology and neurosurgery.
      ].
      The most direct and causal link between the hypothalamus and human emotional states has been reported anecdotally in the neurosurgical literature about deep brain stimulation (DBS) for the treatment of refractory cluster headaches. Schoenen and colleagues [
      • Schoenen J.
      • Di Clemente L.
      • Vandenheede M.
      • Fumal A.
      • De Pasqua V.
      • Mouchamps M.
      • et al.
      Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action.
      ] reported a case of a patient who had “panic attack” during implantation of hypothalamic DBS electrodes. Bartsch and colleagues [
      • Bartsch T.
      • Pinsker M.O.
      • Rasche D.
      • Kinfe T.
      • Hertel F.
      • Diener H.C.
      • et al.
      Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase series.
      ] reported two patients implanted with the hypothalamic electrodes who experienced “panic” as a side effect of stimulation. The episodes were not further described. A similar case was reported by Rasche and colleagues [
      • Bartsch T.
      • Pinsker M.O.
      • Rasche D.
      • Kinfe T.
      • Hertel F.
      • Diener H.C.
      • et al.
      Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase series.
      ] who observed tachycardia, diplopia, and “panic attacks” during the insertion of DBS electrodes in the hypothalamus. Wilent and colleagues [
      • Wilent W.B.
      • Oh M.Y.
      • Buetefisch C.M.
      • Bailes J.E.
      • Cantella D.
      • Angle C.
      • et al.
      Induction of panic attack by stimulation of the ventromedial hypothalamus.
      ] reported panic attacks in response to stimulation of the hypothalamus in the vicinity of ventromedial hypothalamus in a patient undergoing bilateral implantation of DBS electrodes for morbid obesity. The patient had a dramatic increase in anxiety, blood pressure, and heart rate, accompanied by hyperventilation and nausea. Franzini and colleagues [
      • Franzini A.
      • Ferroli P.
      • Leone M.
      • Bussone G.
      • Broggi G.
      Hypothalamic deep brain stimulation for the treatment of chronic cluster headaches: a series report.
      ] reported a patient who reported “I feel near to death”; “I am at the edge of the end” when DBS power exceeded a certain threshold. Elias and colleagues [
      • Elias G.J.B.
      • Giacobbe P.
      • Boutet A.
      • Germann J.
      • Beyn M.E.
      • Gramer R.M.
      • et al.
      Probing the circuitry of panic with deep brain stimulation: connectomic analysis and review of the literature.
      ] examined a patient with obsessive-compulsive disorder who experienced panic attacks during inferior thalamic peduncle stimulations in the operating room and concluded that panic responses were seen with volume of stimulation impinging primarily on the tuberal hypothalamus. While the above studies report momentary observations largely inside the operating rooms as the surgeons insert and trial the DBS probes, a prospective study of a larger cohort of patients with Alzheimer's disease [
      • Neudorfer C.
      • Elias G.J.B.
      • Jakobs M.
      • Boutet A.
      • Germann J.
      • Narang K.
      • et al.
      Mapping autonomic, mood and cognitive effects of hypothalamic region deep brain stimulation.
      ], reported that the stimulations targeting the hypothalamus around the post-commissural fornix and 5 mm from the midline caused “various subjective effects” and more importantly, these subjective symptoms were spatially separable clusters involving distinct hypothalamic and extrahypothalamic loci. Of note, in this study, only 4.7% of cases reported stimulation-induced fear when the volume of stimulation encroached on the ventral part of the hypothalamus. These studies combined provide compelling evidence that in some cases, the stimulation of the human hypothalamus may induce negative emotions such as fear.
      Here, we provide an in depth causal account of the feelings associated with the stimulation of the hypothalamus in the vicinity of the ventromedial nucleus. Combining electrophysiological and imaging connectivity studies and experimental psychological analyses in this rare case, we offer an account of the types of negative emotions that may be induced by the electrical stimulation of the human hypothalamus and how these targeted local stimulations in the hypothalamus may cause changes in a brain-wide selective anatomical and functional circuitry.

      2. Material and methods

      Subject S20_150: The patient was a 31-year-old female with twenty-one years history of seizures. Witnesses reported seizures starting with sounds of “giggling” followed by arm movements. Several medications failed to control the patient's seizures, and hence, the patient was referred to Stanford University Medical Center for further workup. Structural magnetic resonance imaging (MRI) revealed subtle structural abnormality in the left frontal region with overlapping subtle hypometabolism on positron emission tomography (PET/MR). Ictal single-photon emission computerized tomography (SPECT) showed a possible left frontal focus while high density EEG with 256 electrodes suggested a source of epileptiform spikes in the frontal lobes bilaterally. Magnetoencephalography (MEG) showed multiple left frontal dipoles. A meeting was held among practicing epileptologists, epilepsy neurosurgeons, neuroradiology and neuropsychology experts and a consensus decision was made to implant the patient's brain with intracranial electrodes in the suspected cortical regions such as the frontal lobe, limbic lobe including medial temporal lobe, insula, anterior and posterior cingulate. The hypothalamus was also chosen as clinical targets since there were reports from early on that the patient might have had precocious puberty and “gelastic seizures”. See detailed clinical diagnostic summary in Table S1.
      Electrodes: We used stereo-EEG procedure with depth electrodes (0.86 mm in diameter; 2.29 mm height; 3–5 mm inter-electrode center-to-center distance made by AdTech). The patient was implanted with 17 electrodes totaling 170 recording sites.
      Anatomical Localization of Electrodes: Post-operative CT image were merged with high-resolution structural MRI (GE 3-T, 0.9 mm slices axially, T1-weighted SPGR sequence) to localize electrode positions co-registered to each subject's head space, allowing for precise anatomical localization of electrodes [
      • Hermes D.
      • Miller K.J.
      • Noordmans H.J.
      • Vansteensel M.J.
      • Ramsey N.F.
      Automated electrocorticographic electrode localization on individually rendered brain surfaces.
      ]. Electrode contact locations were established in relation to the anatomical information provided by the T1 anatomical template.
      Intracranial Electrical Stimulation Procedure (iES): Patient underwent iES as part of a routine clinical mapping procedure to determine localization of function and seizure focus. In this patient, iES was systematically delivered to every electrode contact in a pseudo-random order to which the patient was blinded. Bipolar stimulation was delivered using an alternating square wave current applied across two adjacent electrodes at 50 Hz, 2–6 mA current, and pulse width of 300 μ s for only 1 s. These were below the threshold to induce after-discharges. Occasional sham stimulations were also delivered to control for demand characteristics. During sham stimulation, the experimenter behaved exactly as during veridical stimulation, adjusting settings on the stimulator and pressing the same buttons, followed by the same standardized questions about any changes in the patient's experience, the only difference being that no current was actually delivered. Following each iES pulse or sham stimulation, patients were asked standardized, open-ended questions about any experiences evoked (e.g., “Did you notice anything?” or “Any change?“), with occasional follow-up questions, as needed, to further clarify the character of effects. Specific iES parameters and elicited effects (or lack thereof) were logged for each stimulation.
      Corticocortical Evoked Potential (CCEP): As detailed in our prior reports [
      • Shine J.M.
      • Kucyi A.
      • Foster B.L.
      • Bickel S.
      • Wang D.
      • Liu H.
      • et al.
      Distinct patterns of temporal and directional connectivity among intrinsic networks in the human brain.
      ,
      • Parvizi J.
      • Braga R.M.
      • Kucyi A.
      • Veit M.J.
      • Pinheiro-Chagas P.
      • Perry C.
      • et al.
      Altered sense of self during seizures in the posteromedial cortex.
      ], single pulse stimulations were performed with a bipolar setup using a cortical stimulator while the subjects were awake and resting. Fifty single pulses of electrical current (6 mA biphasic, 300 μs/phase) were delivered between pairs of adjacent electrodes at a frequency of 0.5 Hz. Data were recorded with a Nihon Kohden system using a sampling rate of 1000 Hz. The recording system included a bandpass filter of 0.08–300 Hz to exclude slow varying and high frequency effects. Electrical potentials were simultaneously measured in all other electrodes with a sampling rate of 1000 Hz. Electrode signals were first re-referenced to a bipolar montage. Evoked responses in non-stimulated electrodes were then segmented into 325 ms epochs (25 ms pre-stimulus and 300 ms post-stimulus) which were time-locked to the delivery of the stimulus. Time series data were normalized to the mean and standard deviation of the first 20 ms of the epoch (i.e., −25 ms to −5 ms) and averaged over all trials of a given stimulation. Because the direction of activity is ambiguous in data collected from bipolar electrodes, we chose the sign of the time series so that the maximum evoked response was positive [
      • Keller C.J.
      • Honey C.J.
      • Megevand P.
      • Entz L.
      • Ulbert I.
      • Mehta A.D.
      Mapping human brain networks with cortico-cortical evoked potentials.
      ]. Finally, peaks were detected using MATLAB's peak detection algorithm. A significant response was defined as a prominence greater than 7 times the standard deviation of the baseline mean (i.e., pre-stimulus time window) for each time series. All time-series which did not show a significant response were discarded from the analysis.
      Ethics and Safety of Electrical Stimulations: Approval for conducting the proposed research was obtained through the Stanford University Institutional Review Board. Patient signed informed consent for participation in our study Patient gave additional consent to release her video for publication or teaching purposes. None of the procedures described in our study introduced any additional risks to the patients. The implantation of electrodes in the hypothalamus and elsewhere in the brain was part of standard of care at our medical center and was motivated solely by clinical needs. The decision to move forward with invasive monitoring and about the approximate location of electrodes was made in a consensus meeting with neurosurgeons, epileptologists, neuropsychologists, psychiatrists, and radiologists in unison. A meeting was held among practicing epileptologists, epilepsy neurosurgeons, neuroradiology and neuropsychology experts and a consensus decision was made to implant the patient's brain with intracranial electrodes in the suspected cortical regions along with the medial temporal lobe structures as well as the hypothalamus since there were reports from early on that the patient might have had precocious puberty and “gelastic seizures”. The procedure of electrical stimulation was also performed as part of a routine clinical procedure in which we deliver electrical pulses various suspected locations while probing if the patient experienced typical seizure auras. In this patient's case, stimulation of the hypothalamus did not cause auras or any ictal events. The electrical brain stimulation used in this study is routinely employed in clinical practice with an excellent safety profile [
      • Goldstein H.E.
      • Smith E.H.
      • Gross R.E.
      • Jobst B.C.
      • Lega B.C.
      • Sperling M.R.
      • et al.
      Risk of seizures induced by intracranial research stimulation: analysis of 770 stimulation sessions.
      ,
      • Gordon B.
      • Lesser R.P.
      • Rance N.E.
      • Hart Jr., J.
      • Webber R.
      • Uematsu S.
      • et al.
      Parameters for direct cortical electrical stimulation in the human: histopathologic confirmation.
      ]. The amount of electrical charge delivery per pulse was always kept within established safe limits (below 30 μC/cm2/pulse) [
      • Agnew W.F.
      • Yuen T.G.
      • McCreery D.B.
      Morphologic changes after prolonged electrical stimulation of the cat's cortex at defined charge densities.
      ,
      • Babb T.L.
      • Kupfer W.
      Phagocytic and metabolic reactions to intracerebral electrical stimulation of rat brain.
      ]. To mitigate any unwanted risk, physicians were at the bedside during the stimulation experiments and monitored the safety of the patient.
      Intracranial EEG Resting State Connectivity: Functional connectivity analysis was performed using slow fluctuations of high-frequency broadband (HFB; 70–170 Hz) power amplitude signals, as described previously [
      • Kucyi A.
      • Schrouff J.
      • Bickel S.
      • Foster B.L.
      • Shine J.M.
      • Parvizi J.
      Intracranial electrophysiology reveals reproducible intrinsic functional connectivity within human brain networks.
      ]. Power line noise of 60 Hz and its harmonics was filtered out (zero-phase, third-order butterworth filter with band-stops of 57–63, 117 to 123 and 177–183 Hz) followed by referencing to the common average signal. Time-frequency decomposition was performed using the Morlet wavelet transform method (five cycles) for frequencies within the 70–170 Hz range spaced in 10 Hz increments. The distribution of power amplitude estimates was normalized by the log ratio of the whole time series within each recording session, followed by averaging of normalized estimates across all frequencies within the 70–170 Hz range. The HFB power amplitude was then filtered between 0.1 and 1 Hz (zero-phase, fourth-order butterworth filter). Functional connectivity was computed as the Pearson correlation coefficient of continuous, filtered HFB power amplitude time series between pairs of electrodes. Functional connectivity values were averaged between two resting state runs with durations of 4.4 and 6.2 min.
      Imaging Processing and Probabilistic Tractography: A 3T MRI scan (Premier, GE Healthcare, Milwaukee, Wisconsin) was obtained throughout the entire cranial volume. Diffusion-weighted images (DWI) were acquired from the patient prior to electrode placement (1.5 mm isotropic, TR/TE = 4641/59.6 ms, 128 directions uniformly distributed on the sphere, b = 1500 s/mm2). Thin-cut CT images were obtained after depth electrode placement. Electrode localization was performed using the thin-cut post-operative CT scan co-registered to preoperative MRI. The thin-cut postoperative CT and the DWI were co-registered to the T1-weighted images using boundary-based registration. Preprocessing of the DWI data was performed using the FSL suite [
      • Jenkinson M.
      • Beckmann C.F.
      • Behrens T.E.
      • Woolrich M.W.
      • Smith S.M.
      ,
      • Andersson J.L.
      • Skare S.
      • Ashburner J.
      How to correct susceptibility distortions in spin-echo echo-planar images: application to diffusion tensor imaging.
      ,
      • Smith S.M.
      • Jenkinson M.
      • Woolrich M.W.
      • Beckmann C.F.
      • Behrens T.E.
      • Johansen-Berg H.
      • et al.
      Advances in functional and structural MR image analysis and implementation as FSL.
      ]. The ‘topup’ and ‘eddy’ functions were used to correct images for motion and geometric distortions. FSL's Bayesian Estimation of Diffusion Parameters Obtained using Sampling Techniques (BedpostX) was used to process the data for probabilistic tractography [
      • Behrens T.E.
      • Berg H.J.
      • Jbabdi S.
      • Rushworth M.F.
      • Woolrich M.W.
      Probabilistic diffusion tractography with multiple fibre orientations: what can we gain?.
      ]. To quantify the DWI-based structural connectivity of cortical regions engaged by hypothalamic stimulation, we performed probabilistic tractography using FSL's Probtrackx2, with distance correction. The seed mask was estimated from the bipolar stimulation parameters. Spheric volumes (2 mm-radius) centered in the voxel coordinates of each recording electrode were used separately as a target. A total of 5000 seed points per voxel were used to generate streamlines, and we recorded the number streamlines that reached each target (i.e., recording electrodes) for further analysis. Tractography results were considered reliable when at least 10 of the generated sample streamlines reached the target, a threshold that has been used in previous probabilistic tracking studies [
      • Tschentscher N.
      • Ruisinger A.
      • Blank H.
      • Diaz B.
      • von Kriegstein K.
      Reduced structural connectivity between left auditory thalamus and the motion-sensitive planum temporale in developmental dyslexia.
      ,
      • Heiervang E.
      • Behrens T.E.
      • Mackay C.E.
      • Robson M.D.
      • Johansen-Berg H.
      Between session reproducibility and between subject variability of diffusion MR and tractography measures.
      ]. To assess whether responses to single-pulse stimulation were related to the tractography results, we plotted the correlation between the Time to First Peak and the streamlines-weighted fractional anisotropy, as defined by the sum of the voxel-wise number of streamlines multiplied by their respective fractional anisotropy. The tractography was run in both directions between the two electrodes and the result of each was averaged. Since our iEEG connectivity measurements were specifically representative of interactions between our stimulation region and a pair of electrode contacts, we refrained from using standardized metrics of voxel-wise microstructure alone. Weighting the fractional anisotropy by the number of streamlines was applied to account for the likelihood of voxel-wise microstructure measurements pertaining to that specific connection. This was also important to avoid having connectivity measurements biased by the microstructural heterogeneity between voxels encompassing different axonal pathways.

      3. Results

      A 31-year-old female patient (Subject S20_150) was studied during a presurgical evaluation for refractory epilepsy with intracranial depth electrodes implanted in cortical and subcortical sites including the hypothalamus (Fig. 1). For clinical information please see Table S1. The source of seizures was localized to a region of the left frontal lobe, and the hypothalamus was found to be void of any epileptic discharges. During one week of intracranial EEG recordings in this patient, we performed targeted stimulation of the hypothalamus and other brain regions as part of a clinical procedure to determine if the hypothalamic stimulations would cause the subject's typical epileptic auras. In the electrical stimulation procedure, we used standard clinical parameters of 300 μ s pulse width, 50Hz frequency, 1–3s duration, and amplitude starting from 2 mA and increasing by 1 mA. The duration of 50Hz stimulations was kept at 1 s across trials. Upon stimulation of the hypothalamus (electrode LHYP1, i.e., the most ventral and medial contact, Fig. 1) the subject reported stereotyped (dose dependent) changes in her affective state with clear expression of an overwhelming negative state, which she described as a “ball of emotions” that was instantaneous and nearly simultaneous with the delivery of a short train (1 s) of electrical pulses to the hypothalamus - but could linger for minutes (Fig. 2). As seen on Video 1, the subject explained that this “ball of emotion” started in the thoracic regions as either localized (with lower currents) or spread bilaterally to her entire body (with higher currents).
      Fig. 1
      Fig. 1Localization of Electrodes and Anatomical Organization within the Hypothalamus. Location of LHYP1 (A) and LHYP2 (B) electrodes in the left hypothalamus are shown in sagittal (top) and coronal (lower) images of the patient's brain. (C) shows the organization of the hypothalamic nuclei in sagittal (upper) and coronal (lower) views. The first electrode is estimated to be close to the infundibular nucleus while the second electrode is in the proximity of ventromedial, tuberomammillary and lateral hypothalamic subregions. (D) shows a diagram of depth electrodes implanted in the hypothalamus. The shaft of electrodes contains platinum contacts (black cylinders) along its course. See the text for discussions about local spread of electricity and propagation of the electrical charge to anatomically and functionally connected brain sites.
      Fig. 2
      Fig. 2Timeline of Stimulation. The precise time of stimulation and elicited responses are shown here. Shaded boxes indicate the times at which the patient reported that the effect of earlier stimulations was lingering.
      The following is/are the supplementary data related to this article:
      Upon probing the details of emotions that overwhelmed her, she clearly rated a high degree of feeling shame, embarrassment, sadness, and fear, but not anger, guilt or grief (Video 1, Table S2&S3). When the patient was asked about specific events in her life that would cause emotions similar to the ones she experienced during the stimulation, she reported that the stimulation of the hypothalamus induced an affective state akin to what she experienced when she lost her pet (who used to be her closest friend); or when she experienced a seizure in the public with people watching her, and especially if her parents were also witnessing it.
      The stimulation effects in the left anterior medial hypothalamus (involving electrode LHYP1 and 2) were reproducible with repeated stimulations and did not occur with sham stimulation (i.e., zero electrical current). The affective-state induced by stimulation was replicated with repeated stimulations at 5 mA, but the unpleasant severe reaction induced with 6 mA stimulation could not be repeated for ethical reasons given the intensity of the patient's response. Importantly, we confirmed scalability of the affective state by titrating the magnitude of electrical current delivered to the hypothalamus (see dose effect in Video 1) as well as changing the anatomy of the electrical field in the millimeter space. For instance, bipolar stimulation of the left hypothalamic electrode pairs of LHYP1 and LHYP2 at 2 mA caused no change in subjective experience; at 3 mA caused lightheadedness and the patient felt something weird that she could not describe; and above 4 mA, caused changes in her affective state that were consciously felt and reported. Stimulation of electrode pair LHYP2 and LHYP3 (0.7 mm dorsal and lateral to the stimulated site) only caused changes in her affective state above 5 mA but the patient also reported face tingling. Stimulation of more dorsal electrodes did not cause any changes in her affective state.
      We could not determine lateralization effect with high confidence because a) the electrodes were not placed entirely symmetrically, and b) the stimulation of the right hypothalamus was performed after the stimulation of the left, and thus we cannot rule out the possibility that any change in her affective state was due to lingering effects of prior stimulations in the left hypothalamus. We noticed that the stimulation of the right hypothalamic electrodes, RHYP1 and RHYP2, above 5 mA caused a sensation of shivering on the right side of the patient's body involving her face and her limbs but stimulation of RHYP2 and RHYP3 at 3 mA caused light-headedness and a weak emotional change. Increasing the current between this pair led to unpleasant olfactory hallucination, and we had to stop the procedure.
      We emphasize that the effect of electrical stimulation is only reliable when all the following criteria are present: 1) the effect is replicable across repeated real trials, 2) the effect is not observed during sham trials, 3) the effect is not seen with stimulation of control sites, and 4) the effect follows a dose effect. Based on these criteria, we believe effects seen after stimulation of RHYP 10–9 and RHYP 2–3 were not replicable, and the singular effects reported by the patient were more likely due to lingering effects of LHYP2 stimulation (Fig. 2). In terms of LHYP 3–2, we are also mindful that the electrical charge affected similar populations as LHYP1-2 or LHYP 2-1 since LHYP2 contact was common in all three combinations.
      We estimated the electrode LHYP1/2 (the most ventral and medial) to be close to the infundibular nucleus while the second electrode is in the proximity of ventromedial, tuberomammillary and lateral hypothalamic subregions (Fig. 1). However, we are uncertain about the size of electrical field during our stimulation with varying parameters. Based on in-vivo measurements in the human brain with stimulation of subdural electrodes in the occipital lobe [
      • Winawer J.
      • Parvizi J.
      Linking electrical stimulation of human primary visual cortex, size of affected cortical area, neuronal responses, and subjective experience.
      ], and the modeling work in the field of DBS [
      • Butson C.R.
      • McIntyre C.C.
      Role of electrode design on the volume of tissue activated during deep brain stimulation.
      ], we estimate that our stimulation with 6 mA created an ellipsoid electrical field with a diameter of 2–3 mm (Fig. S2). Since we cannot ascertain the extent to which hypothalamic sub-structure, sub-structures, or fibers of passage were affected by our stimulation, we use the term “hypothalamus” in the remainder of the text. Nevertheless, the effect of stimulation must have been somewhat anatomically precise since changes in the affective state were only induced by the stimulation of some, but not all, hypothalamic electrodes.
      Given that electrical charges delivered to a given brain region travel along the hardwired neuroanatomical pathways connected with the site of stimulation [
      • Borchers S.
      • Himmelbach M.
      • Logothetis N.
      • Karnath H.O.
      Direct electrical stimulation of human cortex - the gold standard for mapping brain functions?.
      ], we probed the pattern of propagation of electrical charges delivered to the hypothalamus in all cortical sites sampled by intracranial electrodes implanted for epilepsy mapping purposes. To do this, we applied repeated single electrical pulses in the hypothalamic site (LHYP1-2) and measured evoked responses in 168 brain recording sites. Upon stimulation of the hypothalamic seed region, we could detect significant evoked responses in amygdala, hippocampus, ventromedial prefrontal cortex, anterior cingulate, ventral anterior insula, orbitofrontal cortex, the dorsal posterior insula as well as the contralateral hypothalamus (Fig. 3). All other recording sites failed to show significant evoked responses after hypothalamic stimulation. Importantly, the speed of propagation varied by site. The amygdala and hippocampus received the earliest and strongest responses while the posterior insula had the most delayed responses. Further, we analyzed the symmetry in the speed of communication from the hypothalamus (LHYP1-2) to cortical sites (“forward” direction) with the connections into the same hypothalamic site when stimulating the same cortical sites (i.e., “forward” direction). We found bi-directional connectivity, but importantly, the backward direction was faster than the forward response with the difference in time greater for slower forward response times (R = 0.86. p < .0001).
      Fig. 3
      Fig. 3Connectivity of the human hypothalamus measured with three different methods We measured the strength of connectivity of the hypothalamic stimulated site with other recording sites using CCEP (Cortico-cortical evoked potentials), DWI-based tractography-based structural connectivity, and intracranial EEG resting state connectivity. Details of each approach are provided in Online Methods. Our findings reveal a remarkable pattern of connectivity across different modalities. When repeated single electrical pulses were delivered to the hypothalamic area, significant responses were evoked in the amygdala (AMY), hippocampus (Hipp), ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), ventral anterior insula (vaINS), orbitofrontal cortex (ORB), dorsal posterior insula (dpINS). The time to first peak of these evoked responses varied. Earlier responses indicate strong monosynaptic connections. Fractional anisotropy weighted by streamline count values in 106. We used spearman's rank correlation because of non-normal distribution of data and only a few datapoints and because the correlations are not clearly linear. We also chose to run one-sided comparisons given the hypothesis-driven nature of the analysis (we expect time to Tpeak1 to decrease with correlation) and small sample size (n = 15 electrode pairs) did not leave enough power for two-sided stats: We found Time to Peak to have a significant negative correlation with tractography connectivity (rho = −0.44, p = .049, one-sided), and a negative trend correlation with iEEG connectivity (rho = −0.38, p = .0803, one-sided). Tractography and iEEG connectivity measures were positively correlated (rho = 0.52; p = .023, one-sided).
      Next, we examined the correlation between the time of evoked responses and the measures of structural as well as functional connectivity. We examined the structural connectivity of the left anterior hypothalamic site (LHYP 1–2) with the other brain regions that had shown evoked responses when the hypothalamic site was stimulated with single pulse electrical stimulation. For this, we used probabilistic tractography using patient-specific, high-resolution DWI. For the measure of functional connectivity, we relied on the iEEG resting state functional connectivity between the same hypothalamic and brain regions. As seen in Fig. 3, we found a general pattern for faster connections (i.e., lower time-to-first-peak of evoked responses following single-pulse stimulation) between electrode pairs with higher resting state iEEG and DWI-based structural connectivity. Notably, we have previously reported on the relationship between resting state intra-network versus inter-network connections and the measure of CCEP [
      • Veit M.J.
      • Kucyi A.
      • Hu W.
      • Zhang C.
      • Zhao B.
      • Guo Z.
      • et al.
      Temporal order of signal propagation within and across intrinsic brain networks.
      ] and we have shown that the tractography-based structural connectivity of volume of stimulated tissue within the posterior hypothalamus is markedly different than the connectivity profile of more ventromedial region [
      • Kakusa B.
      • Saluja S.
      • Dadey D.Y.A.
      • Barbosa D.A.N.
      • Gattas S.
      • Miller K.J.
      • et al.
      Electrophysiology and structural connectivity of the posterior hypothalamic region: much to learn from a rare indication of deep brain stimulation.
      ].
      Lastly, to investigate if the stimulation of the cortical structures connected with the hypothalamus would elicit identical responses seen with hypothalamic stimulation, we performed similar electrical stimulation procedure and delivered high frequency pulses in the insula, anterior cingulate, ventromedial prefrontal cortex, amygdala, and the hippocampus, and failed to elicit the same responses. We have previously published a review of 100 years of electrical stimulation literature [
      • Selimbeyoglu A.
      • Parvizi J.
      Electrical stimulation of the human brain: perceptual and behavioral phenomena reported in the old and new literature.
      ] and have summarized our observations from the stimulation of 1476 subdural and 61 depth electrodes spanning these cortical regions [
      • Fox K.C.R.
      • Shi L.
      • Baek S.
      • Raccah O.
      • Foster B.L.
      • Saha S.
      • et al.
      Intrinsic network architecture predicts the effects elicited by intracranial electrical stimulation of the human brain.
      ]. There is evidence that the stimulation of several cortical targets especially the ACC [
      • Caruana F.
      • Gerbella M.
      • Avanzini P.
      • Gozzo F.
      • Pelliccia V.
      • Mai R.
      • et al.
      Motor and emotional behaviours elicited by electrical stimulation of the human cingulate cortex.
      ] and OFC [
      • Fox K.C.R.
      • Yih J.
      • Raccah O.
      • Pendekanti S.L.
      • Limbach L.E.
      • Maydan D.D.
      • et al.
      Changes in subjective experience elicited by direct stimulation of the human orbitofrontal cortex.
      ] can induce negative emotions. However, we are unaware of any accounts of complex negative emotions incorporating somatic and affective changes such as the combination of shame, embarrassment, sadness and fear - similar to what we observed from the stimulation of the hypothalamus-being induced by the stimulation of these cortical structures.

      4. Discussion

      Our observations in this single subject provide novel information about the causal effects of hypothalamic stimulation and provide important data relevant to current theories of emotion. It builds on a long line of evidence from animal studies and clinical observations suggesting a causal role for the hypothalamus in engendering emotional states. We are mindful that our study is limited as it was conducted on a single subject who was being evaluated in the clinical setting. Further research is necessary to determine whether our findings in this single subject are generalizable and transferable. Despite its limitations, however, our observations are noteworthy on several grounds.
      We observed that the onset of the subjective affective state was instantaneous and nearly simultaneous with the delivery of a short train (1 s) of electrical pulses to the hypothalamus. We then observed that the patient tried to verbalize the feelings she experienced by using events from her past experience. As such, our observations may be consistent with a two-tiered emotional process. First, there is an instantaneous affective state which occurs as a result of, and simultaneously with, induced changes in the brain state. Second, there is a relatively delayed process involving cognitive associations, linguistic labeling, and possibly appraisal and or re-appraisal. Our observation in this subject demonstrates that the emotion experienced by the patient was instantaneous with, and caused by, a change in the state of the hypothalamus and structures connected with it. This is consistent with biological theories of emotion [
      • Panksepp J.
      Affective neuroscience: the foundations of human and animal emotions.
      ]. As the subject reported changes in her entire body (starting from her chest and radiating to the limbs), we hypothesize that the hypothalamic stimulation may have elicited changes in the body state via direct connections to the autonomic nervous system, or by changes in hormonal state, or by changing the activity of brain structures representing the body - without reaching the body itself (i.e., as-if-body loop [
      • Damasio A.R.
      Descartes' error.
      ]). Consistent with the psychological constructivist theories of emotion [
      • Gross JJW K.
      Emotion regulation and psychopathology: a conceptual framework.
      ,
      • Feldman Barret L.
      How emotions are made.
      ], we also clearly demonstrate that the subject continued to cognitively evaluate the experience based on her past memories and associations. Future experimental work in a larger number of subjects is needed to test the validity of the proposed two-tiered model.
      Our observations add another line of evidence regarding precise feelings that can be elicited by electrical stimulation of the brain. For instance, it is known that: 1) emotions with varied valence can also be elicited by the electrical stimulation of different parts of the ACC [
      • Caruana F.
      • Gerbella M.
      • Avanzini P.
      • Gozzo F.
      • Pelliccia V.
      • Mai R.
      • et al.
      Motor and emotional behaviours elicited by electrical stimulation of the human cingulate cortex.
      ] and OFC [
      • Fox K.C.R.
      • Yih J.
      • Raccah O.
      • Pendekanti S.L.
      • Limbach L.E.
      • Maydan D.D.
      • et al.
      Changes in subjective experience elicited by direct stimulation of the human orbitofrontal cortex.
      ]; 2) changes in the subject's mood by the stimulation of the subgenual cingulate area [
      • Mayberg H.S.
      • Lozano A.M.
      • Voon V.
      • McNeely H.E.
      • Seminowicz D.
      • Hamani C.
      • et al.
      Deep brain stimulation for treatment-resistant depression.
      ]; 3) emotional facial expressions [
      • Selimbeyoglu A.
      • Parvizi J.
      Electrical stimulation of the human brain: perceptual and behavioral phenomena reported in the old and new literature.
      ] and a complex set of cognitive, affective, and physical signs termed as “will to persevere” [
      • Parvizi J.
      • Rangarajan V.
      • Shirer W.R.
      • Desai N.
      • Greicius M.D.
      The will to persevere induced by electrical stimulation of the human cingulate gyrus.
      ] by the stimulation of the dorsal anterior cingulate; 4) feelings of unreality, fear, anxiety, and disgust [
      • Selimbeyoglu A.
      • Parvizi J.
      Electrical stimulation of the human brain: perceptual and behavioral phenomena reported in the old and new literature.
      ,
      • Motomura K.
      • Terasawa Y.
      • Natsume A.
      • Iijima K.
      • Chalise L.
      • Sugiura J.
      • et al.
      Anterior insular cortex stimulation and its effects on emotion recognition.
      ,
      • Papagno C.
      • Pisoni A.
      • Mattavelli G.
      • Casarotti A.
      • Comi A.
      • Fumagalli F.
      • et al.
      Specific disgust processing in the left insula: new evidence from direct electrical stimulation.
      ] by the stimulation of the insula; and 5) feelings of loneliness, fear, anger, anxiety, levitation, or lightness [
      • Selimbeyoglu A.
      • Parvizi J.
      Electrical stimulation of the human brain: perceptual and behavioral phenomena reported in the old and new literature.
      ] by the stimulation of the amygdala. Moreover, our findings are in agreement with recent studies in a large group of subjects documenting that the subjective reports elicited by electrical stimulation of the brain are reliable and reproducible (if applied to the same functional brain hubs) across subjects [
      • Selimbeyoglu A.
      • Parvizi J.
      Electrical stimulation of the human brain: perceptual and behavioral phenomena reported in the old and new literature.
      ,
      • Fox K.C.R.
      • Parvizi J.
      Fidelity of first-person reports following intracranial neuromodulation of the human brain: an empirical assessment of sham stimulation in neurosurgical patients.
      ], are network specific [
      • Fox K.C.R.
      • Shi L.
      • Baek S.
      • Raccah O.
      • Foster B.L.
      • Saha S.
      • et al.
      Intrinsic network architecture predicts the effects elicited by intracranial electrical stimulation of the human brain.
      ], and are dose dependent with respect to both intensity and type of emotion [
      • Yih J.
      • Beam D.E.
      • Fox K.C.R.
      • Parvizi J.
      Intensity of affective experience is modulated by magnitude of intracranial electrical stimulation in human orbitofrontal, cingulate, and insular cortex.
      ].
      It is important to emphasize, however, that our current report of subjective affective states induced by localized electrical stimulation does not necessarily indicate that those subjective states themselves are “localizable” to a discrete brain region. As shown here, electrical discharges delivered to the hypothalamus were readily propagated to other brain structures (the extent of which sampled was limited to clinical decision-making) such as the amygdala, hippocampus, insula, cingulate, and prefrontal regions where we also had recording contacts available. Of note, the time of signal propagation (i.e., within hundreds of milliseconds) matched the instantaneous change in the subject's emotional expression and affective change. However, this is purely hypothetical since we could not measure the precise time of the subject's affective change in milliseconds, and we could not correlate those subjective changes with the electrophysiological changes induced in any of the mentioned brain regions. It is noteworthy, however, that the profile of connectivity between the hypothalamus and some of these brain structures match precisely the evidence from anatomical tracing studies in non-human mammals including primates (Fig. 4) [
      • Saper C.
      Hypothalamus.
      ,
      • Swaab D.F.
      • Hofman M.A.
      • Lucassen P.J.
      • Purba J.S.
      • Raadsheer F.C.
      • Van dN.
      • et al.
      Functional neuroanatomy and neuropathology of the human hypothalamus. [Review] [101 refs].
      ]. Based on these observations, we may hypothesize that the subjective mental contents reported by our patient were elicited by the engagement of a distributed, yet anatomically discrete, brain system.
      Fig. 4
      Fig. 4Map of the anatomical connectivity of the hypothalamus. Here we made our best effort to visualize the extant evidence available from rodent and primate neuroanatomical tracing studies pertaining to the anatomical connectivity of the hypothalamus (original references in Saper 2012).
      The subject reported a complex set of negative emotions including sadness, fear, embarrassment, and shame. The distinction between shame and guilt is noteworthy because shame is an individualized and contextualized emotion that has to do with the subject's view of self while guilt has to do with behavior. It is also noteworthy that our finding is in direct contrast to the observations of the so-called sham rage associated with the stimulation of the hypothalamus in cats and rodents. Several possible explanations for this distinction may be offered. First, our stimulation may have been too coarse compared to stimulations in animals, though we believe this is unlikely. Earlier hypothalamic stimulations in the non-primate brains leading to classic conclusions about sham rage [
      • Hess W.R.
      • Akert K.
      Experimental data on role of hypothalamus in mechanism of emotional behavior.
      ] were performed with even coarser stimulations. Second, the animals seen from human perspective to have sham rage may have been experiencing a more complex feeling than merely rage, but they were unable to report it. Perhaps our anthropocentric interpretation of their emotional behavior may not have been the same as their emotional experience. This alternative is in line with modern views of non-human intelligence and mind [
      • de Waal F.B.
      Are we smart enough to know how smart animals are?.
      ] but is very difficult to prove or refute. Relevant to this, the evidence suggests that rage behavior in animals being stimulated in their hypothalamus is dependent on several variables and may be absent if certain requirements are not met. For instance, the rage behavior is not seen if the stimulation occurs when the animal is actively in a consummatory phase of mating [
      • Lin D.
      • Boyle M.P.
      • Dollar P.
      • Lee H.
      • Lein E.S.
      • Perona P.
      • et al.
      Functional identification of an aggression locus in the mouse hypothalamus.
      ]. A third possibility is that the stimulation effect may be subject dependent. While Subject S20_150 was able to control her behavioral response, others might exhibit rage akin to what is seen in humans. We believe this is also unlikely because when the subject was probed to rate the intensity of various emotions (in the scale of 0–10) she rated anger at 2. Finally, another alternative explanation, which we believe is more likely, may have to do with the differences in the neural architecture (e.g., the rest of the brain) within which the hypothalamus resides and functions. Although the hypothalamus is highly conserved during the course of brain evolution [
      • Saper C.
      Hypothalamus.
      ,
      • Butler A.B.
      • Hodos W.
      Comparative vertebrate neuroanatomy; evolution and adaptation.
      ], it is differently “positioned” in the human brain than in the non-human brain. The human hypothalamus is inter-connected and receives communication from a different set of structures in the human brain than in the non-human mammalian brains. In other words, the range of associative information with which the human hypothalamus operates (e.g., afferents to the hypothalamus from other cortical areas such as the prefrontal cortex) is significantly different than the ones in non-human mammalian brains. Associations we acquire in our culture and personal life may, for example, sway the way the hypothalamic influence is contextualized as evidenced by the patient description of events in her own life that would cause feelings akin to the ones that we induced with the stimulation of her hypothalamus.

      5. Conclusion

      Our observations shows that stimulation of the hypothalamus in a human brain leads to the subjective experience of shame, sadness, and fear. Our work also provides unique insight into hypothalamic connectivity in a human brain by combining single-pulse electrical stimulation, tractography, and iEEG. Based on our observations, we anticipate that future systematic studies in a larger cohort of subjects will reveal causal importance of the human hypothalamus for complex set of emotions. Our results remind us that subcortical structures in the human brain, such as the hypothalamus, ought to be seen as functional units within a broader human telencephalon [
      • Parvizi J.
      Corticocentric myopia: old bias in new cognitive sciences.
      ].

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      CRediT authorship contribution statement

      Josef Parvizi: Conceptualization, Methodology, Investigation, Resources, Writing – original draft, Visualization, Supervision, Project administration, and, Funding acquisition. Michael J. Veit: Methodology, Validation, Formal analysis, Investigation, Writing – review & editing, Visualization. Daniel A.N. Barbosa: Methodology, Validation, Formal analysis, Investigation, Writing – review & editing, Visualization. Aaron Kucyi: Methodology, Validation, Formal analysis, Investigation, Writing – review & editing, Visualization. Claire Perry: Investigation, Data curation, Writing – review & editing, Visualization. Jonathon J. Parker: Investigation, Writing – review & editing. Rajat S. Shivacharan: Investigation, Writing – review & editing. Fengyixuan Chen: Validation, Formal analysis, Visualization. James J. Gross: Conceptualization, Writing – review & editing, Supervision. Robert Fisher: Resources, Writing – review & editing. Jennifer A. McNab: Methodology, Software, Validation, Formal analysis, Investigation, Resources, Supervision. Jessica Falco-Walter: Resources, Writing – review & editing. Casey H. Halpern: Conceptualization, Methodology, Investigation, Resources, Writing – original draft, Supervision, Project administration, and, Funding acquisition.

      Declaration of competing interest

      Nothing to report.

      Acknowledgments

      We thank members of the Stanford Epilepsy Monitoring Unit for assistance with data collection. This work was supported by National Science Foundation [ BCS1358907 ].

      Appendix A. Supplementary data

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