An orexigenic subnetwork within the human hippocampus.

Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive processing1-4. This function has been reported to be mediated at least in part by lateral hypothalamic inputs, including those involving orexigenic lateral hypothalamic neuropeptides, such as melanin-concentrating hormone5,6. This circuit, however, remains elusive in humans. Here we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus and converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues, and this modulation was specific to the dorsolateral hippocampus. Structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behaviour revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders.

Incidence and Outcomes of Posterior Circulation Involvement in Moyamoya Disease.

BACKGROUND: Moyamoya disease (MMD) is a progressive, occlusive disease of the internal carotid arteries and their proximal branches, with the subsequent development of an abnormal vascular network that is rupture-prone. Steno-occlusive changes in the posterior cerebral arteries (PCAs) may contribute to worsened outcomes in patients with MMD; however, there is little information on the incidence and natural history of posterior circulation MMD (PCMMD). We describe clinical PCMMD characteristics in a large cohort of patients with MMD. METHODS: We retrospectively reviewed patients with MMD treated between 1991 and 2019 at a large academic medical center. Demographics, perioperative outcomes, and radiological phenotypes were recorded for 770 patients. PCA disease was graded as either 0 (no disease), 1 (mild), 2 (moderate), or 3 (severe or occluded) based on cerebral angiography. Patients with angiographically confirmed MMD diagnosis with at least 6 months follow-up and completion of revascularization surgery were included; patients with intracranial atherosclerosis, intracranial dissection, vasculitis, and undefined inflammatory processes were excluded. The presence of stenosis/occlusion was graded radiographically to assess for disease progression and the prevalence of risk factors related to reduced progression-free survival. RESULTS: In all, 686 patients met the inclusion criteria, with PCA disease identified in 282 (41.1%) patients. Of those 282 patients with PCMMD, disease severity ranged from 99 (35.1%) with mild, 72 (25.5%) with moderate, and 111 (39.4%) with severe. The total number of postoperative complications was significantly associated with PCMMD severity (P=0.0067). Additionally, PCMMD severity correlated with worse postoperative modified Rankin Scale scores (P<0.0001). At a mean follow-up of 6.0±3.9 (range, 0.1-25.0) years, a total of 60 (12.6%) patients showed new/worsening PCMMD. The overall postoperative, progression-free survival in patients with PCMMD was 95.4% at 1 year, 82.4% at 3 years, 68.8% at 5 years, and 28.3% at 10 years, with prognostic factors for progression including preoperative PCMMD status, history of tobacco use, and hypertension (P<0.0001, P<0.001, and P<0.0001, respectively). CONCLUSIONS: PCA disease involvement in MMD is associated with higher rates of ischemic perioperative complications and worsened functional outcomes, likely due to reduced collateral flow. Ten-year progression of PCA disease is highly likely and should be monitored throughout follow-up; future studies will assess the impact of PCA disease progression on long-term outcomes.

Aberrant impulse control circuitry in obesity.

The ventromedial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) circuit has been implicated in impulsive reward-seeking. This disinhibition has been implicated in obesity and often manifests as binge eating, which is associated with worse treatment outcomes and comorbidities. It remains unclear whether the vmPFC-NAc circuit is perturbed in impulsive eaters with obesity. Initially, we analyzed publicly available, high-resolution, normative imaging data to localize where vmPFC structural connections converged within the NAc. These structural connections were found to converge ventromedially in the presumed NAc shell subregion. We then analyzed multimodal clinical and imaging data to test the a priori hypothesis that the vmPFC-NAc shell circuit is linked to obesity in a sample of female participants that regularly engaged in impulsive eating (i.e., binge eating). Functionally, vmPFC-NAc shell resting-state connectivity was inversely related to body mass index (BMI) and decreased in the obese state. Structurally, vmPFC-NAc shell structural connectivity and vmPFC thickness were inversely correlated with BMI; obese binge-prone participants exhibited decreased vmPFC-NAc structural connectivity and vmPFC thickness. Finally, to examine a causal link to binge eating, we directly probed this circuit in one binge-prone obese female using NAc deep brain stimulation in a first-in-human trial. Direct stimulation of the NAc shell subregion guided by local behaviorally relevant electrophysiology was associated with a decrease in number of weekly episodes of uncontrolled eating and decreased BMI. This study unraveled vmPFC-NAc shell circuit aberrations in obesity that can be modulated to restore control over eating behavior in obesity.

The role of dopamine in reward-related behavior: shining new light on an old debate.

The role dopamine plays in reward-related behaviors has been debated for decades. Heymann et al. (Heymann G, Jo YS, Reichard KL, McFarland N, Chavkin C, Palmiter RD, Soden ME, Zweifel LS. Neuron 105: 909-920, 2020) identify subpopulations of dopamine-producing neurons that separately mediate reward association and motivation. Their results help demonstrate that dopamine signaling may partake in both reinforcement learning and incentive salience functions, instantiated by neuropeptide-defined subpopulations of the ventral tegmental area with different projection targets.

Impact of dupilumab prescribing on utilization of medical and surgical therapies for chronic rhinosinusitis with nasal polyps.

KEY POINTS: Increased dupilumab utilization coincided with decreased ESS in patients with CRSwNP between 2019 and 2021. One potential confounder was the concurrent COVID-19 pandemic, which may have negatively impacted surgery utilization rates.

Diffusion Magnetic Resonance Imaging Tractography Guides Investigation of the Zona Incerta: A Novel Target for Deep Brain Stimulation.

BACKGROUND: The zona incerta (ZI) is a subcortical structure primarily investigated in rodents that is implicated in various behaviors, ranging from motor control to survival-associated activities, partly due to its integration in multiple neural circuits. In the current study, we used diffusion magnetic resonance imaging tractography to segment the ZI and gain insight into its connectivity in various circuits in humans. METHODS: We performed probabilistic tractography in 7T diffusion MRI on 178 participants from the Human Connectome Project to validate the ZI's anatomical subdivisions and their respective tracts. K-means clustering segmented the ZI based on each voxel's connectivity profile. We further characterized the connections of each ZI subregion using probabilistic tractography with each subregion as a seed. RESULTS: We identified 2 dominant clusters that delineated the whole ZI into rostral and caudal subregions. The caudal ZI primarily connected with motor regions, while the rostral ZI received a topographic distribution of projections from prefrontal areas, notably the anterior cingulate and medial prefrontal cortices. We generated a probabilistic ZI atlas that was registered to a patient-participant's magnetic resonance imaging scan for placement of stereoencephalographic leads for electrophysiology-guided deep brain stimulation to treat their obsessive-compulsive disorder. Rostral ZI stimulation improved the patient's core symptoms (mean improvement 21%). CONCLUSIONS: We present a tractography-based atlas of the rostral and caudal ZI subregions constructed using high-resolution diffusion magnetic resonance imaging from 178 healthy participants. Our work provides an anatomical foundation to explore the rostral ZI as a novel target for deep brain stimulation to treat refractory obsessive-compulsive disorder and other disorders associated with dysfunctional reward circuitry.

Striatal dopamine integrates cost, benefit, and motivation.

Striatal dopamine (DA) release has long been linked to reward processing, but it remains controversial whether DA release reflects costs or benefits and how these signals vary with motivation. Here, we measure DA release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) while independently varying costs and benefits and apply behavioral economic principles to determine a mouse's level of motivation. We reveal that DA release in both structures incorporates both reward magnitude and sunk cost. Surprisingly, motivation was inversely correlated with reward-evoked DA release. Furthermore, optogenetically evoked DA release was also heavily dependent on sunk cost. Our results reconcile previous disparate findings by demonstrating that striatal DA release simultaneously encodes cost, benefit, and motivation but in distinct manners over different timescales. Future work will be necessary to determine whether the reduction in phasic DA release in highly motivated animals is due to changes in tonic DA levels.

Abnormal Subjective and Audiometric Auditory Function in Migraine.

OBJECTIVE: To identify if migraine is associated with auditory deficits and if the auditory profile of migraine is distinct from other pain syndromes, such as chronic pain. STUDY DESIGN: Cross-sectional, retrospective. SETTING: A total of 5273 respondents of the 1999 to 2004 National Health and Nutrition Examination Survey. METHODS: Regression analyses assessed the association between migraine (n = 1245) and chronic pain (n = 430) status with subjectively endorsed hearing loss, tinnitus, pure-tone average (PTA) at 500, 1000, 2000, and 4000 Hz, and subjective-audiometric hearing mismatch (endorsed hearing loss but with a PTA ≤ 25 dB), correcting for confounding factors. RESULTS: Migraine was associated with increased tinnitus (adjusted odds ratio [aOR] = 1.77, 95% confidence interval [CI]: 1.47-2.13, p < .001) and subjective hearing loss (aOR = 1.58, 95% CI: 1.29-1.94, p < .001). Migraine was associated with higher PTA (ß = .89, p = .023). Migraine decreased the PTA threshold at which individuals endorsed subjective hearing loss (ß = -1.94, p = .013) and was associated with a more subjective-audiometric hearing mismatch (aOR = 1.50, 95% CI: 1.18-1.89, p < .001). Chronic pain was not associated with tinnitus (aOR = 1.26, 95% CI: 0.97-1.63, p = 0.079), subjective hearing loss (aOR = 0.94, 95% CI: 0.71-1.23, p = .64), changes in PTA (ß = -.22, p = .69), altered PTA threshold for endorsing hearing loss (ß = 1.40, p = .19), or subjective-audiometric hearing mismatch (aOR = 0.98, 95% CI: 0.70-1.34, p = .88). CONCLUSION: Migraine is associated with both worse pure-tone audiometry and higher sensitivity to changes in hearing ability, suggesting both peripheral and central auditory function abnormalities. In contrast, patients with chronic pain did not demonstrate these abnormalities. The etiology of abnormal auditory processing in migraine may be different from that of other pain syndromes.

Human habit neural circuitry may be perturbed in eating disorders.

Circuit-based mechanisms mediating the development and execution of habitual behaviors involve complex cortical-striatal interactions that have been investigated in animal models and more recently in humans. However, how human brain circuits implicated in habit formation may be perturbed in psychiatric disorders remains unclear. First, we identified the locations of the sensorimotor putamen and associative caudate in the human brain using probabilistic tractography from Human Connectome Project data. We found that multivariate connectivity of the sensorimotor putamen was altered in humans with binge eating disorder and bulimia nervosa and that the degree of alteration correlated with severity of disordered eating behavior. Furthermore, the extent of this circuit aberration correlated with mean diffusivity in the sensorimotor putamen and decreased basal dopamine D2/3 receptor binding potential in the striatum, consistent with previously reported microstructural changes and dopamine signaling mediating habit learning in animal models. Our findings suggest a neural circuit that links habit learning and binge eating behavior in humans, which could, in part, explain the treatment-resistant behavior common to eating disorders and other psychiatric conditions.

Safety and Efficacy of Induced Hypertension and Hypervolemia in Preventing Neurologic Complications After Combined Direct and Indirect Bypass in Hemorrhagic-Onset Moyamoya Disease.

BACKGROUND: Perioperative management of blood pressure in patients undergoing surgical revascularization for moyamoya disease (MMD) remains a controversial topic. We evaluated the safety and efficacy of induced hypertension and hypervolemia (IHH) in preventing neurologic complications during the perioperative period after direct surgical revascularization in a large hemorrhagic-onset moyamoya disease (HOMMD) cohort. METHODS: We retrospectively reviewed a prospectively managed departmental database of all HOMMD patients treated between 1987 and 2019. The study included 122 direct surgical revascularization patients. Patients were separated into groups on the basis of the presence or absence of IHH therapy and evaluated for occurrence of 30-day risk of transient neurologic events (TNEs), ischemic, and hemorrhagic complications. RESULTS: Two-hundred and three revascularization procedures were performed on 122 patients for HOMMD treatment. Nineteen TNEs (9.4% of procedures) were observed in 18 (14.8%) patients. Two patients (1.6% and 1.0% of procedures) suffered from ischemic complications and 1 (0.8% and 0.5% of procedures) from hemorrhagic complications. No differences between groups in the severity, duration of TNEs, or length of hospital stay were noted. No patient in the IHH therapy group experienced a recurring TNE or readmission after discharge; however, this was not statistically significant owing to the small sample size. There were no differences in the rates of ischemic or hemorrhagic complications between groups with or without IHH therapy (P = 0.46 and 0.54, respectively). CONCLUSIONS: Induced hypertension and hypervolemia appear safe in HOMMD. There were no significant differences in complication or TNE rates between the groups with or without IHH therapy. While we believe it is important to employ IHH therapy in MMD patients who present with ischemic symptoms, these findings suggest that prophylactic IHH therapy may not be necessary in MMD patients presenting with hemorrhage.

Perturbations of language network connectivity in primary progressive aphasia.

Aphasias are caused by disruption in structural integrity and interconnectivity within a large-scale distributed language network. We investigated the distribution and behavioral consequences of altered functional connectivity in three variants of primary progressive aphasia (PPA). The goal was to clarify relationships among atrophy, resting connectivity, and the resulting behavioral changes in 73 PPA and 33 control participants. Three core regions of the left perisylvian language network: the inferior frontal gyrus (IFG), middle temporal gyrus (MTG), and anterior temporal lobe (ATL) were evaluated in agrammatic (PPA-G), logopenic (PPA-L), and semantic (PPA-S) PPA variants. All PPA groups showed decreased connectivity between IFG and MTG. The PPA-S group also showed additional loss of connectivity strength between ATL and the other language regions. Decreased connectivity between the IFG and MTG nodes in PPA-G remained significant even when controlled for the effect of atrophy. In the PPA group as a whole, IFG-MTG connectivity strength correlated with repetition and grammar scores, whereas MTG-ATL connectivity correlated with picture naming and single-word comprehension. There was no significant change in the connectivity of homologous regions in the right hemisphere. These results show that language impairments in PPA are associated with perturbations of functional connectivity within behaviorally concordant components of the language network. Altered connectivity in PPA may reflect not only the irreversible loss of cortical components indexed by atrophy, but also the dysfunction of remaining neurons.