Sandbox/cognitive impairment in HIV

# Overview
HIV enters the brain early on in the infection. It is thought that HIV uses a Trojan horse mechanism to enter the brain. Normally, the blood brain barrier (BBB) serves as a protective mechanism by preventing entry of foreign substances; disruption of the BBB by HIV contributes to the progression of infection. The virus is able to enter the brain through infected cells that pass through the BBB to replace the immune cells surrounding the blood supply in the brain.  When infected, immune cells are able to better migrate into tissues compared to uninfected cells. Infected microglia add to the production of the virus. This activation of the microglia may contribute to the process of neuropathogenesis that spreads the infection to nearby cells. Other cells that can get infected include the astrocytes, which can trigger bystander cellular dysfunction and apoptosis, further compromising the blood brain barrier. The toxicity spreads through a gap junction-dependent mechanism.

# Anatomical areas involved
- HIV is associated with pathological changes in mainly subcortical and fronto-striatal areas of the brain, including the basal ganglia, deep white matter, and hippocampal regions.
- Neuroimaging studies of HIV patients indicate that significant volume reductions are apparent in the frontal white matter, whereas subcortically, hypertrophy is apparent in the basal ganglia, especially the putamen.
- Some studies suggest loss of brain volume in cortical and subcortical regions even in asymptomatic HIV patients and patients who were on stable treatment.  Cerebral brain volume is associated with factors related to duration of the disease and CD4 nadir; patients with a longer history of chronic HIV and higher CD4 nadir present with greater cerebral atrophy.
- CD4 lymphocyte counts have also been related to greater rates of brain tissue loss.
- Current factors, such as plasma HIV RNA, have been found to be associated with brain volumes as well, especially with regards to basal ganglia volume and total white matter.
- Changes in the brain may be ongoing but asymptomatic, that is with minimal interference in functioning, making it difficult to diagnose HIV-associated neurocognitive disorders in the early stages.

# Behavioral aspects of neurocognitive Impairments

## Cognitive impairments
- Cognitive impairments associated with HIV occur in the domains of attention, memory, verbal fluency, and visuospatial construction. Specifically for memory, the lowered activity of the hippocampus changes the basis for memory encoding and affects mechanisms such as long-term potentiation.
- Severity of impairment in different domains varies depending on whether or not a patient is being treated with HAART or monotherapy.
- Studies have shown that patients exhibit cognitive deficits consistent with dysfunction of fronto-striatal circuits including associated parietal areas, the latter of which may account for observed deficits in visuospatial function.

## Psychological Dysfunction
- In addition to cognitive impairments, psychological dysfunction is also noted. For example, patients with HIV have higher rates of clinical depression and alexithymia, i.e., difficulty processing or recognizing ones own emotions.  Patients also have more difficulty recognizing facial emotions.
- Without combination antiretroviral therapy, cognitive impairments increase with successive stages of HIV.  HIV patients in early stages show mild difficulties in concentration and attention.  In advanced cases of HIV-associated dementia, speech delay, motor dysfunction, and impaired thought and behavior are observed. Specifically, lower motor speeds were found to correlate with hypertrophy of the right putamen.
- The diagnosis of HIV-associated neurocognitive impairment is made using clinical criteria after considering and ruling out other possible causes.  The severity of neurocognitive impairment is associated with nadir CD4, suggesting that earlier treatment to prevent immunosuppression due to HIV may help prevent HIV-associated neurocognitive disorders.

# Supportive Trial Data
- A study by Melrose et al. (2008) examined the integrity of the fronto-striatal circuitry that underlies executive functioning in HIV.
Participants in the study were diagnosed with HIV three months to sixteen years before the study. Ten out of eleven patients were on antiretroviral medication and none scored within the demented range on the HIV Dementia Scale. It was found that HIV+ patients showed less activity within the ventral prefrontal cortex (PFC) and left dorsolateral PFC. There was reduced connectivity between the left caudate and ventral PFC and between the left caudate and dorsolateral PFC compared to healthy controls. Additionally, there was hypoactivation of the left caudate in the HIV+ patients. In the control group, there was correlation between caudate activity and executive functioning as shown by performance on neuropsychological testing. Further analysis of the pathways in the HIV+ group involving left caudate showed reduced functional connectivity between the left caudate and globus pallidus (basal ganglia output nucleus). This dysfunction with the basal ganglia and PFC may explain the executive function and semantic event sequencing task impairments noted in HIV+ patients included in this study.
The study also investigated parietal activation.  It was found that anterior parietal activation in HIV+ patients was slightly anterior to that in control participants, which follows the idea that HIV causes a reorganization of the attention network leading to cognitive impairments. Additionally, the anterior parietal activity showed a relationship with caudate functioning, which implicates a compensatory mechanism set forth when damage to the fronto-striatal system occurs .
Overall, this study showed that HIV in the brain is associated with cognitive impairments. Damage to the fronto-striatal system may underlie cognitive problems including executive function and sequencing tasks.
- Participants in the study were diagnosed with HIV three months to sixteen years before the study. Ten out of eleven patients were on antiretroviral medication and none scored within the demented range on the HIV Dementia Scale. It was found that HIV+ patients showed less activity within the ventral prefrontal cortex (PFC) and left dorsolateral PFC. There was reduced connectivity between the left caudate and ventral PFC and between the left caudate and dorsolateral PFC compared to healthy controls. Additionally, there was hypoactivation of the left caudate in the HIV+ patients. In the control group, there was correlation between caudate activity and executive functioning as shown by performance on neuropsychological testing. Further analysis of the pathways in the HIV+ group involving left caudate showed reduced functional connectivity between the left caudate and globus pallidus (basal ganglia output nucleus). This dysfunction with the basal ganglia and PFC may explain the executive function and semantic event sequencing task impairments noted in HIV+ patients included in this study.
- The study also investigated parietal activation.  It was found that anterior parietal activation in HIV+ patients was slightly anterior to that in control participants, which follows the idea that HIV causes a reorganization of the attention network leading to cognitive impairments. Additionally, the anterior parietal activity showed a relationship with caudate functioning, which implicates a compensatory mechanism set forth when damage to the fronto-striatal system occurs .
- Overall, this study showed that HIV in the brain is associated with cognitive impairments. Damage to the fronto-striatal system may underlie cognitive problems including executive function and sequencing tasks.
- Another area of impairment due to fronto-striatal dysfunction is in the area of emotion recognition. In a study of HIV+ patients and control adults by Clark et al. (2010), it was shown that HIV patients demonstrate impairments in the recognition of fearful facial expressions. The authors suggested that fronto-striatal abnormalities related to HIV may underlie these impairments.
In identification tasks, administered by Clark et. al (2010), HIV+ patients and control participants were asked to identify different facial emotions and landscapes, with these picture categories matched for image complexity. HIV+ patients did worse than the control group on the facial recognition task but not on landscape identification. In the facial emotion task, fear recognition was significantly worse in the HIV than in the control group.
- In identification tasks, administered by Clark et. al (2010), HIV+ patients and control participants were asked to identify different facial emotions and landscapes, with these picture categories matched for image complexity. HIV+ patients did worse than the control group on the facial recognition task but not on landscape identification. In the facial emotion task, fear recognition was significantly worse in the HIV than in the control group.