Project description:This report describes a Belgian Malinois dog residing in metropolitan Phoenix, Arizona that was presented to a veterinary neurology center with abnormal eye movements as his only clinical sign. On examination, clinical signs were isolated to convergence-retraction nystagmus. A brain MRI was performed which identified two well-demarcated, T2-hypointense and T1-isointense, avidly contrast enhancing mass lesions with moderate to severe perilesional T2 and FLAIR hyperintensity within the left frontal lobe and left dorsal midbrain. Imaging characteristics were most consistent with Coccidioides immitis fungal granulomas and serology was supportive of Coccidioidomycosis infection. The patient's clinical signs resolved quickly with antifungal and anti-inflammatory therapies, and brain granulomas were resolved or resolving on repeat imaging 10 months after initial diagnosis. To the authors' knowledge, this is the first report of convergence-retraction nystagmus secondary to an infectious etiology described in a canine patient.
Project description:We describe the clinical course, with special attention to the disturbance of eye movements, of a 29-year-old man with chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins and anti-GD1b disialosyl antibodies (CANOMAD). Using the magnetic search coil technique, we documented convergence during upward saccades and other features suggestive of dorsal midbrain syndrome. Thus, in common with Miller Fisher syndrome, CANOMAD may present with clinical findings implicating involvement of the central nervous system, which contains ganglioside antigens to anti-GD1b antibodies.
Project description:The hippocampus has been a focus of memory research since H.M's surgery abolished his ability to form new memories, yet its mechanistic role in memory remains debated. Here, we identify a candidate memory mechanism: an anticipatory hippocampal "convergence state", observed while awaiting valuable information, and which predicts subsequent learning. During fMRI, participants viewed trivia questions eliciting high or low curiosity, followed seconds later by its answer. We reasoned that encoding success requires a confluence of conditions, so that hippocampal states more conducive to memory formation should converge in state space. To operationalize convergence of neural states, we quantified the typicality of multivoxel patterns in the medial temporal lobes during anticipation and encoding of trivia answers. We found that the typicality of anticipatory hippocampal patterns increased during high curiosity. Crucially, anticipatory hippocampal pattern typicality increased with dopaminergic midbrain activation and uniquely accounted for the association between midbrain activation and subsequent recall. We propose that hippocampal convergence states may complete a cascade from motivation and midbrain activation to memory enhancement, and may be a general predictor of memory formation.
Project description:ObjectiveNeuronal loss in the substantia nigra pars compacta (SNpc) in Parkinson disease (PD) is not uniform, as dopamine neurons from the ventral tier are lost more rapidly than those of the dorsal tier. Identifying the intrinsic differences that account for this differential vulnerability may provide a key for developing new treatments for PD.MethodsHere, we compared the RNA-sequenced transcriptomes of ~100 laser captured microdissected SNpc neurons from each tier from 7 healthy controls.ResultsExpression levels of dopaminergic markers were similar across the tiers, whereas markers specific to the neighboring ventral tegmental area were virtually undetected. After accounting for unwanted sources of variation, we identified 106 differentially expressed genes (DEGs) between the SNpc tiers. The genes higher in the dorsal/resistant SNpc tier neurons displayed coordinated patterns of expression across the human brain, their protein products had more interactions than expected by chance, and they demonstrated evidence of functional convergence. No significant shared functionality was found for genes higher in the ventral/vulnerable SNpc tier. Surprisingly but importantly, none of the identified DEGs was among the familial PD genes or genome-wide associated loci. Finally, we found some DEGs in opposite tier orientation between human and analogous mouse populations.InterpretationOur results highlight functional enrichments of vesicular trafficking, ion transport/homeostasis and oxidative stress genes showing higher expression in the resistant neurons of the SNpc dorsal tier. Furthermore, the comparison of gene expression variation in human and mouse SNpc populations strongly argues for the need of human-focused omics studies. ANN NEUROL 2020;87:853-868.
Project description:The mechanism underlying the differentiation of the dorsal midbrain into two morphologically and functionally distinct compartments, the inferior colliculus (IC) and superior colliculus (SC), which process auditory and visual information, respectively, remains largely unexplored. By using null and conditional alleles, we uncover the roles of a homeodomain transcription factor Dbx1 in the regulation of IC and SC differentiation. We show that Dbx1 regulates GABAergic neuron development in the dorsal midbrain. In the absence of Dbx1 function, the dorsal-most m1-m2 progenitor domains in the midbrain fail to activate GABAergic neuron-specific gene expression and instead switch to a glutamatergic phenotype. These results identify Dbx1 as a dorsal midbrain-specific GABAergic determinant that regulates the selector genes, Helt, Gata2, and Tal2. Furthermore, we demonstrate that maturation of the dorsal midbrain into the IC and SC is dependent on Dbx1. Null mutation of Dbx1 impairs the identity and fate of IC and SC neurons. Surprisingly, Dbx1 is required for preventing IC into SC fate switch and thus Dbx1-deficient IC neurons undergo acquisition of SC identity. Conditional inactivation of Dbx1 at late developmental phase leads to alteration in the identity and fate of the IC, but not the SC. These results suggest that SC differentiation is dependent on the early function of Dbx1, and that the IC requires the prolonged action for its normal formation. Furthermore, we uncover that Tcf7l2 acts downstream of Dbx1 selectively to promote IC differentiation. Altogether, our study identifies a molecular mechanism underlying spatial and temporal control of dorsal midbrain development.
Project description:Agenesis of the dorsal pancreas (ADP) is an extremely rare congenital anomaly. Human pancreas is formed by ventral and dorsal endodermal buds of the foregut endoderm. The dorsal bud forms the upper part of the head, neck, body, and tail of the pancreas and the ventral bud generates most of the head and uncinate process. ADP is derived from the embryologic failure of the dorsal pancreatic bud to form the pancreatic body and tail. ADP can be related to some diseases and conditions such as pancreatitis, hypoglycemia, and rarely pancreatic tumors. The association between cystic lesions with ADP has previously been reported. Three cases of cystic lesions of the pancreas with ADP were diagnosed clinically based on the imaging features and without any past history of pancreatitis. However, the pathologic diagnosis of resected lesions confirmed pseudocysts without pathologic evidence of tumor. We report 3 cases of pancreatic pseudocysts associated with ADP.
Project description:The dentatothalamic tract connects the dentate nucleus of the cerebellum with the contralateral thalamus and plays a major role in the pathogenesis of tremor. Unilateral lesions of the dentatothalamic pathway may affect its ipsilateral predecussational or its contralateral postdecussational course, which results either in ipsilateral or in contralateral tremor.Here, we present two patients with a unilateral midbrain lesion resulting in bilateral tremor. Both patients presented with severe kinetic tremor.The corresponding unilateral mesencephalic lesion affected both the ipsilateral predecussational and the ipsilateral postdecussational dentatothalamic tract originating from the contralateral dentate nucleus, which is very unusual and has not been outlined clearly before.