Complex negative emotions induced by electrical stimulation of the human hypothalamus.

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.

Deep posteromedial cortical rhythm in dissociation.

Advanced imaging methods now allow cell-type-specific recording of neural activity across the mammalian brain, potentially enabling the exploration of how brain-wide dynamical patterns give rise to complex behavioural states1-12. Dissociation is an altered behavioural state in which the integrity of experience is disrupted, resulting in reproducible cognitive phenomena including the dissociation of stimulus detection from stimulus-related affective responses. Dissociation can occur as a result of trauma, epilepsy or dissociative drug use13,14, but despite its substantial basic and clinical importance, the underlying neurophysiology of this state is unknown. Here we establish such a dissociation-like state in mice, induced by precisely-dosed administration of ketamine or phencyclidine. Large-scale imaging of neural activity revealed that these dissociative agents elicited a 1-3-Hz rhythm in layer 5 neurons of the retrosplenial cortex. Electrophysiological recording with four simultaneously deployed high-density probes revealed rhythmic coupling of the retrosplenial cortex with anatomically connected components of thalamus circuitry, but uncoupling from most other brain regions was observed-including a notable inverse correlation with frontally projecting thalamic nuclei. In testing for causal significance, we found that rhythmic optogenetic activation of retrosplenial cortex layer 5 neurons recapitulated dissociation-like behavioural effects. Local retrosplenial hyperpolarization-activated cyclic-nucleotide-gated potassium channel 1 (HCN1) pacemakers were required for systemic ketamine to induce this rhythm and to elicit dissociation-like behavioural effects. In a patient with focal epilepsy, simultaneous intracranial stereoencephalography recordings from across the brain revealed a similarly localized rhythm in the homologous deep posteromedial cortex that was temporally correlated with pre-seizure self-reported dissociation, and local brief electrical stimulation of this region elicited dissociative experiences. These results identify the molecular, cellular and physiological properties of a conserved deep posteromedial cortical rhythm that underlies states of dissociation.

Detecting silent seizures by their sound.

OBJECTIVE: The traditional approach to interpreting electroencephalograms (EEGs) requires physicians with formal training to visually assess the waveforms. This approach can be less practical in critical settings where a trained EEG specialist is not readily available to review the EEG and diagnose ongoing subclinical seizures, such as nonconvulsive status epilepticus. METHODS: We have developed a novel method by which EEG data are converted to sound in real time by letting the underlying electrophysiological signal modulate a voice tone that is in the audible range. Here, we explored whether individuals without any prior EEG training could listen to 15-second sonified EEG and determine whether the EEG represents seizures or nonseizure conditions. We selected 84 EEG samples to represent seizures (n = 7), seizure-like activity (n = 25), or nonperiodic, nonrhythmic activity (normal or focal/generalized slowing, n = 52). EEGs from single channels in the left and right hemispheres were then converted to sound files. After a 4-minute training video, medical students (n = 34) and nurses (n = 30) were asked to designate each audio sample as "seizure" or "nonseizure." We then compared their performance with that of EEG-trained neurologists (n = 12) and medical students (n = 29) who also diagnosed the same EEGs on visual display. RESULTS: Nonexperts listening to single-channel sonified EEGs detected seizures with remarkable sensitivity (students, 98% ± 5%; nurses, 95% ± 14%) compared to experts or nonexperts reviewing the same EEGs on visual display (neurologists, 88% ± 11%; students, 76% ± 19%). If the EEGs contained seizures or seizure-like activity, nonexperts listening to sonified EEGs rated them as seizures with high specificity (students, 85% ± 9%; nurses, 82% ± 12%) compared to experts or nonexperts viewing the EEGs visually (neurologists, 90% ± 7%; students, 65% ± 20%). SIGNIFICANCE: Our study confirms that individuals without EEG training can detect ongoing seizures or seizure-like rhythmic periodic patterns by listening to sonified EEG. Although sonification of EEG cannot replace the traditional approaches to EEG interpretation, it provides a meaningful triage tool for fast assessment of patients with suspected subclinical seizures.

Gelastic epilepsy and hypothalamic hamartomas: neuroanatomical analysis of brain lesions in 100 patients.

Hypothalamic hamartomas present with isolated fits of ictal laughter (gelastic epilepsy) or a combination of gelastic and other types of seizures. Many of these patients also suffer from cognitive decline, neuropsychiatric comorbidities and precocious puberty. Although there is a large body of anecdotal evidence about hypothalamic hamartomas and gelastic seizures, many questions still remain to be answered. For instance, which specific hypothalamic regions are most affected by the location of hamartomas causing laughing versus other types of seizures? Does the neuroanatomical localization of the lesions differ in cases with only gelastic seizures or a combination of gelastic and other types of seizures? Does the location of the lesions correlate with the presence of precocious puberty, and does the type of lesion influence the severity or the type of seizures? In a retrospective review of clinical and structural neuroimaging data from 100 cases of gelastic epilepsy and hypothalamic hamartoma, we aimed to address these questions by analysing the clinical presentation and the neuroanatomical features of the hypothalamic lesions in these patients. Our findings suggest that in all 100 cases, lesions were centred at the level of the mammillary bodies in the posterior hypothalamus. Compared with the patients with pure gelastic seizures (n = 32), those with gelastic and other types of seizures (n = 68) had significantly longer duration of epilepsy (P < 0.001), whereas age of seizure onset, the volume of lesions and the proximity to the mammillary bodies were not different between the two groups. In contrast, patients with cognitive or developmental impairment and those with precocious puberty had significantly larger lesions involving the anterior and posterior hypothalamus.

Neuroanatomy of pathological laughing and crying: a report of the American Neuropsychiatric Association Committee on Research.

Pathological laughing and crying (PLC) is a clinical condition that occurs in patients with various neurological disorders. It is characterized by the presence of episodic and contextually inappropriate or merely exaggerated outbursts of laughter and/or crying without commensurate feelings. This review provides an in depth analysis of the neuroanatomy of lesions seen in patients with this clinical condition, discusses the relevant functional neuroimaging and electrophysiological stimulation studies in human subjects, and summarizes the current treatment options. It concludes with a presentation of the remaining questions and directions for future research.

Thalamic projections to the posteromedial cortex in the macaque.

The medial parietal, posterior cingulate, and retrosplenial cortices collectively constitute a region of cortex referred to as the posteromedial cortices (PMC). In an effort to shed light on the neuroanatomical organization of the PMC, we undertook a study to identify and analyze the thalamocortical connections of these cortices. Retrograde tracer injections were placed in the posterior cingulate (PCC), retrosplenial (RSC), medial parietal cortices (MPC), and posterior cingulate sulcus (PCS), and the labeling patterns within the thalamus were analyzed. Three afferent projection patterns were observed to the PMC from the thalamus: a PCC/RSC pattern that involved the anterior thalamic nuclei, an MPC pattern that involved the lateral posterior and pulvinar nuclei, and a PCS pattern that involved the ventral thalamic nuclei. Additionally, a shared pattern of projections from the anterior intralaminar nuclei (AILN) and posterior thalamic nuclei (PTN) to all cortical regions of the PMC was observed. Our findings suggest that distinct regions within the PMC are supplied by distinctive patterns of thalamic input, but also share common projections from intralaminar and posterior thalamic sources. In addition, we relate our findings to functional abnormalities in aging and dementia, and address a domain-like pattern of thalamocortical labeling of the PMC that is drawn selectively and collectively from multiple thalamic nuclei.

Diagnosis and management of pathological laughter and crying.

Patients with various neurologic disorders exhibit exaggerated or inappropriate episodes of laughter, crying, or both without an apparent motivating stimulus or in response to stimuli that would not have elicited such an emotional response before the onset of the underlying disease. During these episodes, patients have difficulty controlling their emotional expression according to the contextual information. In contrast, patients with mood disorders have a pervasive and sustained change in their emotional experience and thus exhibit spells of laughter or crying because of an underlying mania or depression. This article focuses on the clinical presentation, diagnosis, prevalence, and proposed pathophysiological mechanisms of and available treatment options for this clinical phenomenon.

Neural connections of the posteromedial cortex in the macaque.

The posterior cingulate and the medial parietal cortices constitute an ensemble known as the posteromedial cortex (PMC), which consists of Brodmann areas 23, 29, 30, 31, and 7m. To understand the neural relationship of the PMC with the rest of the brain, we injected its component areas with four different anterograde and retrograde tracers in the cynomolgus monkey and found that all PMC areas are interconnected with each other and with the anterior cingulate, the mid-dorsolateral prefrontal, the lateral parietal cortices, and area TPO, as well as the thalamus, where projections from some of the PMC areas traverse in an uninterrupted bar-like manner, the dorsum of this structure from the posteriormost nuclei to its rostralmost tip. All PMC regions also receive projections from the claustrum and the basal forebrain and project to the caudate, the basis pontis, and the zona incerta. Moreover, the posterior cingulate areas are interconnected with the parahippocampal regions, whereas the medial parietal cortex projects only sparsely to the presubiculum. Although local interconnections and shared remote connections of all PMC components suggest a functional relationship among them, the distinct connections of each area with different neural structures suggests that distinct functional modules may be operating within the PMC. Our study provides a large-scale map of the PMC connections with the rest of the brain, which may serve as a useful tool for future studies of this cortical region and may contribute to elucidating its intriguing pattern of activity seen in recent functional imaging studies.