Resting state connectivity of the human habenula at ultra-high field

The habenula, a portion of the epithalamus, is implicated in the pathophysiology of depression, anxiety and addiction disorders. Its small size and connection to other small regions prevent standard human imaging from delineating its structure and connectivity with confidence. Resting state functional connectivity is an established method for mapping connections across the brain from a seed region of interest. The present study takes advantage of 7T fMRI to map, for the first time, the habenula resting state network with very high spatial resolution in 32 healthy human participants. Results show novel functional connections in humans, including functional connectivity with the septum and bed nucleus of the stria terminalis (BNST). Results also show many habenula connections previously described only in animal research, such as with the nucleus basalis of Meynert, dorsal raphe, ventral tegmental area (VTA), and periaqueductal grey (PAG). Connectivity with caudate, thalamus and cortical regions such as the anterior cingulate, retrosplenial cortex and auditory cortex are also reported. This work, which demonstrates the power of ultra-high field for mapping human functional connections, is a valuable step toward elucidating subcortical and cortical regions of the habenula network

Neural Substrates of Fear Generalization and Its Associations with Anxiety and Intolerance of Uncertainty

Fear generalization - the tendency to interpret ambiguous stimuli as threatening due to perceptual similarity to a learned threat – is an adaptive process. Overgeneralization, however, is maladaptive and has been implicated in a number of anxiety disorders. Neuroimaging research has indicated several regions sensitive to effects of generalization, including regions involved in fear excitation (e.g., amygdala, insula) and inhibition (e.g., ventromedial prefrontal cortex). Research has suggested several other small brain regions may play an important role in this process (e.g., hippocampal subfields, bed nucleus of the stria terminalis [BNST], habenula), but, to date, these regions have not been examined during fear generalization due to limited spatial resolution of standard human neuroimaging. To this end, the proposed project utilized high resolution spatial resolution of 7T fMRI to (1) characterize the neural circuits involved in threat discrimination and generalization, and (2) examine modulating effects of trait anxiety and intolerance of uncertainty on neural activation during threat generalization. In a sample of 31 healthy undergraduate students, significant positive generalization effects (i.e., greater activation for stimuli with increasing perceptual similarity to a learned threat cue) were observed in the visual cortex, thalamus, habenula and BNST, while negative generalization effects were observed in the dentate gyrus, CA1, CA3, and basal nucleus of the amygdala. Associations with individual differences were limited, though greater generalization in the insula and primary somatosensory cortex was correlated with self-reported anxiety. Overall, findings largely support previous neuroimaging work on fear generalization and provide additional insight into the contributions of several previously unexplored brain regions

High Field fMRI Reveals Thalamocortical Integration of Segregated Cognitive and Emotional Processing in Mediodorsal and Intralaminar Thalamic Nuclei

Thalamocortical loops, connecting functionally segregated, higher order cortical regions, and basal ganglia, have been proposed not only for well described motor and sensory regions, but also for limbic and prefrontal areas relevant for affective and cognitive processes. These functions are, however, more specific to humans, rendering most invasive neuroanatomical approaches impossible and interspecies translations difficult. In contrast, non-invasive imaging of functional neuroanatomy using fMRI allows for the development of elaborate task paradigms capable of testing the specific functionalities proposed for these circuits. Until recently, spatial resolution largely limited the anatomical definition of functional clusters at the level of distinct thalamic nuclei. Since their anatomical distinction seems crucial not only for the segregation of cognitive and limbic loops but also for the detection of their functional interaction during cognitive–emotional integration, we applied high resolution fMRI on 7 Tesla. Using an event-related design, we could isolate thalamic effects for preceding attention as well as experience of erotic stimuli. We could demonstrate specific thalamic effects of general emotional arousal in mediodorsal nucleus and effects specific to preceding attention and expectancy in intralaminar centromedian/parafascicular complex. These thalamic effects were paralleled by specific coactivations in the head of caudate nucleus as well as segregated portions of rostral or caudal cingulate cortex and anterior insula supporting distinct thalamo–striato–cortical loops. In addition to predescribed effects of sexual arousal in hypothalamus and ventral striatum, high resolution fMRI could extent this network to paraventricular thalamus encompassing laterodorsal and parataenial nuclei. We could lend evidence to segregated subcortical loops which integrate cognitive and emotional aspects of basic human behavior such as sexual processing

Neuroimaging at 7 Tesla: a pictorial narrative review

Neuroimaging using the 7-Tesla (7T) human magnetic resonance (MR) system is rapidly gaining popularity after being approved for clinical use in the European Union and the USA. This trend is the same for functional MR imaging (MRI). The primary advantages of 7T over lower magnetic fields are its higher signal-to-noise and contrast-to-noise ratios, which provide high-resolution acquisitions and better contrast, making it easier to detect lesions and structural changes in brain disorders. Another advantage is the capability to measure a greater number of neurochemicals by virtue of the increased spectral resolution. Many structural and functional studies using 7T have been conducted to visualize details in the white matter and layers of the cortex and hippocampus, the subnucleus or regions of the putamen, the globus pallidus, thalamus and substantia nigra, and in small structures, such as the subthalamic nucleus, habenula, perforating arteries, and the perivascular space, that are difficult to observe at lower magnetic field strengths. The target disorders for 7T neuroimaging range from tumoral diseases to vascular, neurodegenerative, and psychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, epilepsy, major depressive disorder, and schizophrenia. MR spectroscopy has also been used for research because of its increased chemical shift that separates overlapping peaks and resolves neurochemicals more effectively at 7T than a lower magnetic field. This paper presents a narrative review of these topics and an illustrative presentation of images obtained at 7T. We expect 7T neuroimaging to provide a new imaging biomarker of various brain disorders

Untangling the dorsal diencephalic conduction system: a review of structure and function of the stria medullaris, habenula and fasciculus retroflexus

The often-overlooked dorsal diencephalic conduction system (DDCS) is a highly conserved pathway linking the basal forebrain and the monoaminergic brainstem. It consists of three key structures; the stria medullaris, the habenula and the fasciculus retrofexus. The frst component of the DDCS, the stria medullaris, is a discrete bilateral tract composed of fbers from the basal forebrain that terminate in the triangular eminence of the stalk of the pineal gland, known as the habenula. The habenula acts as a relay hub where incoming signals from the stria medullaris are processed and subsequently relayed to the midbrain and hindbrain monoaminergic nuclei through the fasciculus retrofexus. As a result of its wide-ranging connections, the DDCS has recently been implicated in a wide range of behaviors related to reward processing, aversion and motivation. As such, an understanding of the structure and connections of the DDCS may help illuminate the pathophysiology of neuropsychiatric disorders such as depression, addiction and pain. This is the frst review of all three components of the DDCS, the stria medullaris, the habenula and the fasciculus retrofexus, with particular focus on their anatomy, function and development

Imaging Habenula Volume in Schizophrenia and Bipolar Disorder

The habenula (Hb), a bilateral nucleus located next to the dorsomedial thalamus, is of particular relevance to psychiatric disorders based on preclinical evidence linking the Hb to depressive and amotivational states. However, studies in clinical samples are scant because segmentation of the Hb in neuroimaging data is challenging due to its small size and low contrast from the surrounding tissues. Negative affective states dominate the clinical course of schizophrenia and bipolar disorder and represent a major cause of disability. Diagnosis-related alterations in the volume of Hb in these disorders have therefore been hypothesized but remain largely untested. To probe this question, we used a recently developed objective and reliable semi-automated Hb segmentation method based on myelin-sensitive magnetic resonance imaging (MRI) data. We ascertained case-control differences in Hb volume from high resolution structural MRI data obtained from patients with schizophrenia (n = 95), bipolar disorder (n = 44) and demographically matched healthy individuals (n = 52). Following strict quality control of the MRI data, the final sample comprised 68 patients with schizophrenia, 32 with bipolar disorder and 40 healthy individuals. Regardless of diagnosis, age, sex, and IQ were not correlated with Hb volume. This was also the case for age of illness onset and medication (i.e., antipsychotic dose and lithium-treatment status). Case-control differences in Hb volume did not reach statistical significance; their effect size (Cohen's d) was negligible on the left (schizophrenia: 0.14; bipolar disorder: −0.03) and small on the right (schizophrenia: 0.34; bipolar disorder: 0.26). Nevertheless, variability in the volume of the right Hb was associated with suicidality in the entire patient sample (ρ = 0.29, p = 0.004) as well as in each patient group (bipolar disorder: ρ = 0.34, p = 0.04; schizophrenia: ρ = 0.25, p = 0.04). These findings warrant replication in larger samples and longitudinal designs and encourage more comprehensive characterization of Hb connectivity and function in clinical populations

A unified model of ketamine’s dissociative and psychedelic properties

OKKetamine is an N-methyl-d-aspartate antagonist which is increasingly being researched and used as a treatment for depression. In low doses, it can cause a transitory modification in consciousness which was classically labelled as ‘dissociation’. However, ketamine is also commonly classified as an atypical psychedelic and it has been recently reported that ego dissolution experiences during ketamine administration are associated with greater antidepressant response. Neuroimaging studies have highlighted several similarities between the effects of ketamine and those of serotonergic psychedelics in the brain; however, no unified account has been proposed for ketamine’s multi-level effects – from molecular to network and psychological levels. Here, we propose that the fast, albeit transient, antidepressant effects observed after ketamine infusions are mainly driven by its acute modulation of reward circuits and sub-acute increase in neuroplasticity, while its dissociative and psychedelic properties are driven by dose- and context-dependent disruption of large-scale functional networks. Computationally, as nodes of the salience network (SN) represent high-level priors about the body (‘minimal’ self) and nodes of the default-mode network (DMN) represent the highest-level priors about narrative self-experience (‘biographical’ self), we propose that transitory SN desegregation and disintegration accounts for ketamine’s ‘dissociative’ state, while transitory DMN desegregation and disintegration accounts for ketamine’s ‘psychedelic’ state. In psychedelic-assisted psychotherapy, a relaxation of the highest-level beliefs with psychotherapeutic support may allow a revision of pathological self-representation models, for which neuroplasticity plays a permissive role. Our account provides a multi-level rationale for using the psychedelic properties of ketamine to increase its long-term benefits.publishersversionepub_ahead_of_prin

A habenula-insular circuit encodes the willingness to act

The decision that it is worth doing something rather than nothing is a core yet understudied feature of voluntary behaviour. Here we study “willingness to act”, the probability of making a response given the context. Human volunteers encountered opportunities to make effortful actions in order to receive rewards, while watching a movie inside a 7 T MRI scanner. Reward and other context features determined willingness-to-act. Activity in the habenula tracked trial-by-trial variation in participants’ willingness-to-act. The anterior insula encoded individual environment features that determined this willingness. We identify a multi-layered network in which contextual information is encoded in the anterior insula, converges on the habenula, and is then transmitted to the supplementary motor area, where the decision is made to either act or refrain from acting via the nigrostriatal pathway

Chronic stress induces activity, synaptic and transcriptional remodeling of the lateral habenula associated with deficits in motivated behaviors

Chronic stress is a major risk factor for the development of depression. In recent years, the lateral habenula (LHb) has emerged as a potential key structure in depression. LHb is connected with dopaminergic neurons in the ventral tegmental area (VTA) and serotoninergic neurons in the dorsal raphe nucleus (DR), and changes in these monoaminergic systems have been associated with depression-related behaviors. In my dissertation, I demonstrate that chronic stress-induced hyperactivity in LHb neurons projecting to VTA is associated with increased passive coping but not anxiety or anhedonia. Moreover, LHb→VTA neurons in mice with increased passive coping show increased burst and tonic firing as well as synaptic adaptations in excitatory inputs from the entopeduncular nucleus (EP). In vivo manipulations of EP→LHb or LHb→VTA neurons also selectively alter passive coping and effort-related motivation. Conversely, dorsal raphe (DR)-projecting LHb neurons do not show chronic stress-induced hyperactivity and are targeted indirectly by the EP. Using single-cell transcriptomics I reveal a set of genes that can collectively serve as biomarkers to identify mice with increased passive coping phenotype and differentiate LHb→VTA from LHb→DR neurons. Together, I provide a set of biological markers at the level of genes, synapses, cells and circuits that define a distinctive chronic stress-induced behavioral phenotype