Hypoactivation in the precuneus and posterior cingulate cortex during ambiguous decision making in individuals with HIV.

People with human immunodeficiency virus (HIV) often have neurocognitive impairment. People with HIV make riskier decisions when the outcome probabilities are known, and have abnormal neural architecture underlying risky decision making. However, ambiguous decision making, when the outcome probabilities are unknown, is more common in daily life, but the neural architecture underlying ambiguous decision making in people with HIV is unknown. Eighteen people with HIV and 20 controls completed a decision making task while undergoing functional magnetic resonance imaging scanning. Participants chose between a certain reward and uncertain reward with a known (risky) or unknown (ambiguous) probability of winning. There were three levels of risk: high, medium, and low. Ambiguous > risky brain activity was compared between groups. Ambiguous > risky brain activity was correlated with emotional/psychiatric functioning in people with HIV. Both groups were similarly ambiguity-averse. People with HIV were more risk-averse than controls and chose the high-risk uncertain option less often. People with HIV had hypoactivity in the precuneus, posterior cingulate cortex (PCC), and fusiform gyrus during ambiguous > medium risk decision making. Ambiguous > medium risk brain activity was negatively correlated with emotional/psychiatric functioning in individuals with HIV. To make ambiguous decisions, people with HIV underrecruit key regions of the default mode network, which are thought to integrate internally and externally derived information to come to a decision. These regions and related cognitive processes may be candidates for interventions to improve decision-making outcomes in people with HIV.

Neurocognitive impairment and gray matter volume reduction in HIV-infected patients.

Although neuropsychological studies of human immunodeficiency virus (HIV)-infected patients have demonstrated heterogeneity in neurocognitive impairment and neuroimaging studies have reported diverse brain regions affected by HIV, it remains unclear whether individual differences in neurocognitive impairment are underpinned by their neural bases. Here, we investigated spatial distribution patterns of correlation between neurocognitive function and regional gray matter (GM) volume across patients with HIV. Thirty-one combination antiretroviral therapy-treated HIV-infected Japanese male patients and 33 age- and sex-matched healthy controls were included in the analysis after strict exclusion criteria, especially for substance use. Fifteen neurocognitive tests were used, and volumetric magnetic resonance imaging was performed. We used voxel-based morphometry to compare GM volume between groups and identify regional GM volumes that correlated with neurocognitive tests across patients. Using the Frascati criteria, 10 patients were diagnosed with asymptomatic neurocognitive impairment, while the others were not diagnosed with HIV-associated neurocognitive disorders. Patients showed a significantly lower performance in five neurocognitive tests as well as significantly reduced GM volume relative to controls, with volume-reduced regions spread diffusely across the whole brain. Different aspects of neurocognitive impairment (i.e., figural copy, finger tapping, and Pegboard) were associated with different GM regions. Our findings suggest a biological background constituting heterogeneity of neurocognitive impairment in HIV infection and support the clinical importance of considering individual differences for tailor-made medicine for people living with HIV.

Pomalidomide-associated progressive multifocal leukoencephalopathy in multiple myeloma: cortical susceptibility-weighted imaging hypointense findings prior to clinical deterioration.

Although there are several case reports of progressive multifocal leukoencephalopathy (PML) in multiple myeloma (MM), there are few reports of cases associated with pomalidomide. Here, we report the case of a 69-year-old female who had received 41 cycles of pomalidomide and dexamethasone treatment for relapsed/refractory IgG-κ MM presented with right-hand weakness; she was diagnosed as pomalidomide-associated PML. Fluid-attenuated inversion recovery (FLAIR) on admission showed high signals in the bilateral front-parietal lobe white matter, with multiple punctate lesions in the vicinity of the main lesions. These punctate pattern findings on FLAIR were similar to that of natalizumab-associated PML. Susceptibility weighted imaging (SWI) showed hypointense rims within the cortex at unaffected sites, in the initial stages. Subsequently, the clinical manifestations deteriorated, and the FLAIR images showed new hyperintense white matter lesions at the sites where cortical SWI hypointense rims were detected on the initial MRI examination. Our patient's serial MRI findings suggest that cortical SWI hypointense rims appear prior to the visible demyelinating white matter lesions in patients with PML.

Low-frequency fluctuation characteristics in rhesus macaques with SIV infection: a resting-state fMRI study.

Simian immunodeficiency virus (SIV)-infected macaque is a widely used model to study human immunodeficiency virus. The purpose of the study is to discover the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) changes in SIV-infected macaques. Seven rhesus macaques were involved in the longitudinal MRI scans: (1) baseline (healthy state); (2) SIV infection stage (12 weeks after SIV inoculation). ALFF and fALFF were subsequently computed and compared to ascertain the changes caused by SIV infection. Whole-brain correlation analysis was further used to explore the possible associations between ALFF/fALFF values and immune status parameters (CD4+ T cell counts, CD4/CD8 ratio and virus load). Compared with the baseline, macaques in SIV infection stage displayed strengthened ALFF values in left precuneus, postcentral gyrus, and temporal gyrus, and weakened ALFF values in orbital gyrus and inferior temporal gyrus. Meanwhile, increased fALFF values were found in left superior frontal gyrus, right precentral gyrus, and superior temporal gyrus, while decreased fALFF values existed in left hippocampus, left caudate, and right inferior frontal gyrus. Furthermore, ALFF and fALFF values in several brain regions showed significant relationships with CD4+ T cell counts, CD4/CD8 ratio, and plasma virus load. Our findings could promote the understanding of neuroAIDS caused by HIV infection, which may provide supplementary evidences for the future therapy study in SIV model.

Vocal emotion processing deficits in HIV-infected individuals.

We aimed to explore the brain imaging correlates of vocal emotion processing in a group of HIV+ individuals and to compare the vocal emotion processing of HIV+ individuals with a group of healthy adults. We conducted multiple linear regressions to determine the cerebral correlates of a newly designed vocal emotion processing test in a sub-group of HIV+ individuals who completed the cerebral magnetic resonance scan (n = 36). Separately, we test whether the association between our test scores and each cerebral measure persisted regardless of the presence of neurocognitive impairment. We also calculated differences in average test scores between the total HIV+ group (n = 100) and a healthy adult group (n = 46). We found a positive association between the test scores and several brain area volumes: right frontal, temporal and parietal lobes, bilateral thalamus, and left hippocampus. We found a negative association between inflammatory markers in frontal white matter and the test scores. After controlling by neurocognitive impairment, several brain area volumes remained positively associated to the prosody test scores. Moreover, the whole HIV+ sample had significantly poorer test scores than healthy adults, but only in the subset of HIV+ individuals with neurocognitive impairment. For the first time, our results suggest that cerebral dysfunctions in particular brain areas involved in the processing of emotional auditory stimuli may occur in HIV+ individuals. These results highlight the need for broad characterization of the neuropsychological consequence of HIV brain damages.

Severe auditory processing disorder secondary to viral meningoencephalitis.

OBJECTIVE: To describe auditory function in an individual with bilateral damage to the temporal and parietal cortex. DESIGN: Case report. STUDY SAMPLE: A previously healthy 17-year old male is described who sustained extensive cortical injury following an episode of viral meningoencephalitis. He developed status epilepticus and required intubation and multiple anticonvulsants. RESULTS: Serial brain MRIs showed bilateral temporoparietal signal changes reflecting extensive damage to language areas and the first transverse gyrus of Heschl on both sides. The patient was referred for assessment of auditory processing but was so severely impaired in speech processing that he was unable to complete any formal tests of his speech processing abilities. Audiological assessment utilizing objective measures of auditory function established the presence of normal peripheral auditory function and illustrates the importance of the use of objective measures of auditory function in patients with injuries to the auditory cortex. CONCLUSIONS: Use of objective measures of auditory function is essential in establishing the presence of normal peripheral auditory function in individuals with cortical damage who may not be able to cooperate sufficiently for assessment utilizing behavioral measures of auditory function.

Decreased MEG beta oscillations in HIV-infected older adults during the resting state.

The introduction of combination antiretroviral therapy significantly reduced the prevalence of the most severe form of HIV-associated neurocognitive disorders (HAND). Despite this decline, 35-70 % of HIV-infected patients continue to develop mild motor and cognitive impairments. Although neuropsychological studies have shown that HAND affects a wide array of cognitive functions, a formal diagnosis is still based on the exclusion of opportunistic infections and other common ailments, as no specific tests or biomarkers are currently available. In this study, we used magnetoencephalography (MEG) to measure neural activity during the resting-state in 15 HIV-infected older patients and a demographically matched group of 15 uninfected controls. MEG is a noninvasive and direct measure of neural activity with excellent spatiotemporal resolution. All MEG data were coregistered to structural magnetic resonance images, corrected for head motion, fitted to a regional-level source model, and subjected to spectral analyses to quantify population-level neural oscillatory activity. We found that HIV-infected persons exhibited decreased beta oscillations in the supplementary motor area bilaterally, paracentral lobule, posterior cingulate, and bilateral regions of the superior parietal lobule relative to healthy controls. Beta oscillations in the posterior cingulate, a critical component of the default mode network, were also positively correlated with patient scores on the memory recall aspect of the Hopkins Verbal Learning Test-Revised. These results demonstrate that chronic HIV infection does not uniformly disturb cortical function, and that neuronal populations in dorsomedial motor and parietal cortices are especially affected. These findings also suggest that resting-state MEG recordings may hold significant promise as a functional biomarker for identifying HAND and monitoring disease progression.

Epstein Barr virus encephalitis: clinical diversity and radiological similarity.

Clinico-radiological features of two patients with cerebrospinal fluid polymerase chain reaction-positive Epstein Barr virus (EBV) encephalitis have been reported. Both the patients presented with fever and altered sensorium, one had visual hallucination, decerebration followed by visual loss and the other had downward ocular deviation and orofacial and upper limb choreiform movement. Magnetic resonance imaging (MRI) revealed parieto-occipital involvement in both the patients. Follow-up MRI at one month was normal in one and revealed regression of lesion in the other. Both the patients, however, had severe neurologic sequelae at 18 months' follow-up. EBV encephalitis may have diverse clinical presentation with characteristic parieto-occipital involvement.

Simian immunodeficiency virus infection in the brain and lung leads to differential type I IFN signaling during acute infection.

Using an accelerated and consistent SIV pigtailed macaque model of HIV-associated neurologic disorders, we have demonstrated that virus enters the brain during acute infection. However, neurologic symptoms do not manifest until late stages of infection, suggesting that immunological mechanisms exist within the CNS that control viral replication and associated inflammation. We have shown that IFN-ß, a type I IFN central to viral innate immunity, is a major cytokine present in the brain during acute infection and is responsible for limiting virus infection and inflammatory cytokine expression. However, the induction and role of IFN-α in the CNS during acute SIV infection has never been examined in this model. In the classical model of IFN signaling, IFN-ß signals through the IFN-α/ß receptor, leading to expression of IFN-α. Surprisingly, although IFN-ß is upregulated during acute SIV infection, we found that IFN-α is downregulated. We demonstrate that this downregulation is coupled with a suppression of signaling molecules downstream of the IFN receptor, namely tyrosine kinase 2, STAT1, and IFN regulatory factor 7, as indicated by either lack of protein phosphorylation, lack of nuclear accumulation, or transcriptional and/or translational repression. In contrast to brain, IFN-α is upregulated in lung and accompanied by activation of tyrosine kinase 2 and STAT1. These data provide a novel observation that during acute SIV infection in the brain, there is differential signaling through the IFN-α/ß receptor that fails to activate expression of IFN-α in the brain.

Brain tumor as an unusual presentation of posttransplant lymphoproliferative disorder.

OBJECTIVES: Posttransplant lymphoproliferative disorder following solid organ transplant is a lifethreatening form of posttransplant malignancy. Its occurrence is typically associated with Epstein-Barr virus and profound immunosuppressive therapy. We describe a case of posttransplant lymphoproliferative disorder in the brain parenchyma, 4 years after renal transplant. CASE REPORT: A 23-year-old man was evaluated for generalized headache 4 years after receiving a deceased donor renal transplant. After initial immunosuppression with tacrolimus and prednisolone, mycophenolate mofetil was added for maintenance immunosuppression. A tumor in the right occipitoparietal lobe was detected by magnetic resonance imaging and excised. Immunohistochemical testing of the tumor revealed B-cell marker and Epstein-Barr virus. After surgery, the dosage of immunosuppressive drugs was reduced, and the patient was treated with chemotherapy and radiotherapy. Our patient is well after treatment. CONCLUSIONS: Reduction in immunosuppressive therapy is an important component of treatment for Epstein-Barr virus-positive posttransplant lymphoproliferative disorder and may lead to remission in early disease. If reduced immunosuppression fails to control early disease, cytotoxic chemotherapy, surgery and radiotherapy, antiviral therapies, and cell-based therapies are other options for treatment.

Severe ataxia as a complication of human parvovirus B19 acute encephalitis in a child.

Human parvovirus B19 generally causes erythema infectiosum in childhood, but it can be associated with unusual findings, particularly in immunocompromised patients. This is a report about an immunocompetent 4-year-old female child affected with acute encephalitis by parvovirus B19, documented by polymerase chain reaction performed on cerebrospinal fluid, who was treated with intravenous immunoglobulins and dexamethasone and who developed a cerebellar syndrome with ataxia, dysmetria, and dysarthria. To the best of the authors' knowledge, this may be the first report of human parvovirus B19 encephalitis complicated by severe ataxia in childhood.

The human immunodeficiency virus reduces network capacity: acoustic noise effect.

OBJECTIVE: Increased acoustic noise (AN) during working memory leads to increased brain activation in healthy individuals and may have greater impact in human immunodeficiency virus (HIV) patients. RESULTS: Compared with control subjects, HIV patients showed reduced AN activation and lower neuronal marker N-acetylaspartate in prefrontal and parietal cortices. Competing use of the working memory network between AN and cognitive load showed lower dynamic range of the hemodynamic responses in prefrontal and parietal cortices in HIV patients. INTERPRETATION: These findings suggest that reduced reserve capacity of the working memory network in HIV patients and additional stress (eg, AN) might exhaust the impaired network for more demanding tasks.

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.

Prevalence and distribution of human herpesvirus 6 variants A and B in adult human brain.

The presence of human herpesvirus 6 (HHV-6) in brain tissues of 40 consecutive post-mortem cases was examined. For each case, autopsy samples were collected from the cerebellum, frontal, temporal, parietal and occipital lobes of both sides of the brain. HHV-6 DNA was detected by nested polymerase chain reaction and characterised into variants A and B. Overall, 97/400 (24.3%) samples were positive for HHV-6 DNA with 16 being variant A and 81 being variant B, but none of the samples harboured both variants. When analysed by patient, 34/40 (85%) had HHV-6 DNA detected in the brain. The viral DNA positivity did not show significant variation with gender and age. Four patients harboured variant A, 23 harboured variant B, and seven had both variants at different positions. The results indicate that both HHV-6A and HHV-6B are neurotropic and human brain may be another site for latency. HHV-6B was detected in brain tissues of a majority (75%) of the studied population and with a widespread distribution within the brain. Although the observed prevalence of HHV-6A in brain is lower (27.5%), in view of its lower seroprevalence, the neuroinvasive potential of variant A may be comparable to that of variant B. Although both variants are potential pathogens for the nervous system, the fact that they can exist, probably for most of the time, as commensals in human brain needs to be considered when interpreting their roles in neuropathology.

Prevalence and distribution of human herpesvirus 7 in normal brain.

Although it has been recognised that human herpesvirus 7 (HHV-7) establishes latent infection in CD4+ T lymphocytes and productive infection in salivary glands, recent data suggest that its in vivo tropism may be more widespread. In this study, the prevalence and distribution of HHV-7 in brain tissues of 30 consecutive post-mortems were examined by nested polymerase chain reaction. For each post-mortem, 10 fresh autopsy tissue samples were collected respectively from the cerebellum, frontal, temporal, parietal, and occipital lobes of both cerebral hemispheres. These patients were aged from 20-95 years (mean = 61.4, SD = 20.2) with a male:female ratio of 2:1. Three patients died of intracranial haemorrhage, the others died of causes unrelated to the central nervous system. Overall, 5% (15/300) of the brain tissue samples were positive for HHV-7 DNA. The positive rates with respect to anatomical positions were similar (0-3/30). When analysed by patient, 36.7% (11/30) were HHV-7 DNA positive. The viral DNA-positive and -negative groups did not show a significant difference in gender or age distribution. The majority (81.8%) of viral DNA-positive patients had HHV-7 DNA detected at only one anatomical position; only two patients had viral DNA detected simultaneously at three anatomical sites. These results suggest that HHV-7 persists in brain tissues of a substantial proportion of the adult population, and in most individuals, its distribution is probably confined to one site rather than pervasive. Further studies to elucidate the role of this ubiquitous virus in neuropathology are warranted.

Diaschisis in chronic viral encephalitis with Koshevnikov syndrome.

The authors report a 61-year-old man with chronic viral encephalitis and Koshevnikov syndrome occurring 42 months after initial symptom of right hemiparesis. Serial computed tomography of the brain showed changes in the attenuation of the left temporal lobe lesion over time. Magnetic resonance images of the brain showed enlargement of left temporoparietooccipital lobes with cortical gyral enhancement on T1-weighted images following intravenous administration of gadolinium-DTPA. 99mTc-HMPAO single-photon emission computerized tomography showed increased radioactivity and hyperperfusion in the left temporoparietal region with paradoxically decreased local tissue perfusion at the contralateral right hemisphere. Follow-up magnetic resonance images of the brain 4 years later showed atrophy of bilateral cerebral hemispheres. We postulate that a "transcallosal diaschisis" with subsequent degeneration is a possible mechanism. A brain biopsy from the left temporal lobe lesion showed pictures compatible with viral encephalitis probably herpes simplex encephalitis.