Cerebral patterns of neuropsychological disturbances in hepatitis C patients.

Neuropsychiatric symptoms and cognitive impairment have been consistently reported in patients with hepatitis C virus (HCV) infection. Since the mechanisms behind remain to be established, the present study attempted to assess whether neuropsychological impairments in HCV-infected patients are accompanied by structural alterations in the brain. Therefore, 19 anti-HCV-antibody-positive women with mild liver disease and 16 healthy controls underwent extensive neuropsychological testing and cranial magnetic resonance imaging (MRI) examination. Nine of the patients and five controls were followed up after 6-7 years. Voxel-based morphometry and magnetization transfer imaging were utilized to study HCV-associated structural gray and white matter changes. The HCV-infected patients had significantly worse fatigue and depression scores and significantly poorer performance on attention and memory tests than controls. The patients displayed gray matter (GM) atrophy in the bilateral insula and thalamus and a profound GM volume increases in the cerebellum. Microstructural GM changes in the insula were also evident by a reduced magnetization transfer ratio. Structural white matter changes were observed along several descending and crossing fiber tracts. Follow-up at 7 years revealed increased GM atrophy in the left amygdala and left parahippocampal regions over time. We conclude that our data provide evidence for structural alterations in the brains of patients with chronic HCV infection. Disturbances of cerebellothalamocortical regions and circuits, linking cerebellar projections to the prefrontal cortex through the thalamus, underpin the emotional and cognitive dysfunction characteristically observed in these patients.

Herpes simplex encephalitis with thalamic, brainstem and cerebellar involvement.

Herpes simplex virus encephalitis is a common and treatable cause of acute encephalitis in all age groups. Certain radiological features such as temporal parenchymal involvement facilitate the diagnosis. The use of herpes simplex virus polymerase chain reaction has expanded the clinical and imaging spectrum. We report the case of a young patient who presented with a movement disorder and predominant involvement of thalami, brainstem and cerebellum on magnetic resonance imaging, and was diagnosed with herpes simplex virus encephalitis. Differentiation from Japanese encephalitis may be difficult in these patients, especially in endemic areas, and may necessitate the use of relevant investigations in all patients.

Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate.

We used transneuronal transport of neurotropic viruses to examine the topographic organization of circuits linking the cerebellar cortex with the arm area of the primary motor cortex (M1) and with area 46 in dorsolateral prefrontal cortex of monkeys. Retrograde transneuronal transport of the CVS-11 (challenge virus strain 11) strain of rabies virus in cerebello-thalamocortical pathways revealed that the arm area of M1 receives input from Purkinje cells located primarily in lobules IV-VI of the cerebellar cortex. In contrast, transneuronal transport of rabies from area 46 revealed that it receives input from Purkinje cells located primarily in Crus II of the ansiform lobule. Thus, both M1 and area 46 are the targets of output from the cerebellar cortex. However, the output to each area of the cerebral cortex originates from Purkinje cells in different regions of the cerebellar cortex. Anterograde transneuronal transport of the H129 strain of herpes simplex virus type 1 (HSV1) revealed that neurons in the arm area of M1 project via the pons to granule cells primarily in lobules IV-VI, whereas neurons in area 46 project to granule cells primarily in Crus II. Together, the findings from rabies and HSV1 experiments indicate that the regions of the cerebellar cortex that receive input from M1 are the same as those that project to M1. Similarly, the regions of the cerebellar cortex that receive input from area 46 are the same as those that project to area 46. Thus, our observations suggest that multiple closed-loop circuits represent a fundamental architectural feature of cerebrocerebellar interactions.

Distribution of rabies antigen in infected brain material: determining the reliability of different regions of the brain for the rabies fluorescent antibody test.

To assist in making recommendations for sampling of brains for the fluorescent antibody test (FAT), a study was conducted to determine the regions of the brain where rabies antigen is found most reliably. Each identifiable part of 252 rabies-positive brains of various species was re-tested using routine FA tests. It was found that there was frequent variation in the quantity of antigen between regions of the brain. The thalamus, pons and medulla were the most reliable parts of the brain as they were positive in all specimens tested. The cerebellum, hippocampus and different parts of the cerebrum were negative in, respectively, 4.5, 4.9 and 3.9-11.1% of positive brains. It is recommended that specimens for rabies diagnosis must include the brain stem. The structure of choice would be the thalamus as it was positive in all specimens and had the most frequent prevalence (97.8%) of abundant antigen. These findings contradict many old studies that state that the hippocampus should be the structure of choice for rabies diagnosis. The current data demonstrate that the reason for the old recommendations is that the hippocampus has the highest frequency of large inclusion bodies, as the reliability of the histological tests used previously depended on inclusion body size.

The inferior parietal lobule is the target of output from the superior colliculus, hippocampus, and cerebellum.

The inferior parietal lobule (IPL) is a functionally and anatomically heterogeneous region that is concerned with multiple aspects of sensory processing and sensorimotor integration. Although considerable information is available about the corticocortical connections to the IPL, much less is known about the origin and importance of subcortical inputs to this cortical region. To examine this issue, we used retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 (HSV1) to identify the second-order neurons in subcortical nuclei that project to the IPL. Four monkeys (Cebus apella) received injections of HSV1 into three different subregions of the IPL. Injections into a portion of the lateral intraparietal area labeled second-order neurons primarily in the superficial (visual) layers of the superior colliculus. Injections of HSV1 into a portion of area 7a labeled many second-order neurons in the CA1 region of the hippocampus. In contrast, virus injections within a portion of area 7b labeled second-order neurons in posterior regions of the dentate nucleus of the cerebellum. These observations have some important functional implications. The IPL is known to be involved in oculomotor and attentional mechanisms, the establishment of maps of extrapersonal space, and the adaptive recalibration of eye-hand coordination. Our findings suggest that these functions are subserved by distinct subcortical systems from the superior colliculus, hippocampus, and cerebellum. Furthermore, the finding that each system appears to target a separate subregion of the IPL provides an anatomical substrate for understanding the functional heterogeneity of the IPL.

Cerebellar projections to the prefrontal cortex of the primate.

The cerebellum is known to project via the thalamus to multiple motor areas of the cerebral cortex. In this study, we examined the extent and anatomical organization of cerebellar input to multiple regions of prefrontal cortex. We first used conventional retrograde tracers to map the origin of thalamic projections to five prefrontal regions: medial area 9 (9m), lateral area 9 (9l), dorsal area 46 (46d), ventral area 46, and lateral area 12. Only areas 46d, 9m, and 9l received substantial input from thalamic regions included within the zone of termination of cerebellar efferents. This suggested that these cortical areas were the target of cerebellar output. We tested this possibility using retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 from areas of prefrontal cortex. Neurons labeled by retrograde transneuronal transport of virus were found in the dentate nucleus only after injections into areas 46d, 9m, and 9l. The precise location of labeled neurons in the dentate varied with the prefrontal area injected. In addition, the dentate neurons labeled after virus injections into prefrontal areas were located in regions spatially separate from those labeled after virus injections into motor areas of the cerebral cortex. Our observations indicate that the cerebellum influences several areas of prefrontal cortex via the thalamus. Furthermore, separate output channels exist in the dentate to influence motor and cognitive operations. These results provide an anatomical substrate for the cerebellum to be involved in cognitive functions such as planning, working memory, and rule-based learning.

Effects of neonatal rat Borna disease virus (BDV) infection on the postnatal development of the brain monoaminergic systems.

Effects of neonatal Borna disease virus infection (BDV) on the postnatal development of brain monoaminergic systems in rats were studied. Tissue content of norepinephrine (NE), dopamine (DA) and its metabolite, 3,4-dihydroxyphenol acetic acid (DOPAC), and serotonin (5-HT) and its metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA) were assayed by means of HPLC-EC in frontal cortex, cerebellum, hippocampus, hypothalamus and striatum of neonatally BDV-infected and sham-inoculated male Lewis rats of 8, 14, 21, 60 and 90 days of age. Both NE and 5-HT concentrations were significantly affected by neonatal BDV infection. The cortical and cerebellar levels of NE and 5-HT were significantly greater in BDV-infected rats than control animals at postnatal days (PND) 60 and 90. Tissue content of NE in hippocampus was unaffected. In hippocampus, neonatally BDV-infected rats had lower 5-HT levels at PND 8 and significantly elevated levels at PND 21 and onwards. Neither striatal levels of 5-HT nor hypothalamic levels of 5-HT and NE were affected by neonatal BDV infection, suggesting that the monoamine systems in the prenatally maturing brain regions are less sensitive to effects of neonatal viral infection. 5-HIAA/5-HT ratio was not altered in BDV-infected rats indicating no changes in the 5-HT turnover in the brain regions damaged by the virus. Neither DA nor DOPAC/DA ratio was affected by neonatal BDV infection in any of the brain regions examined. The present data demonstrate significant and specific alterations in monoaminergic systems in neonatally BDV-infected rats. This pattern of changes is consistent with the previously reported behavioral abnormalities resulting from neonatal BDV infection.