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Cognitive Neurorehabilitation of HIV-associated Neurocognitive Disorders: A Qualitative Review and Call to Action
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Neuropsychology Review
Received: 7 December 2012 / Accepted: 27 January 2013
Erica Weber, Kaitlin Blackstone & Steven Paul Woods
University of California, San Diego
".....studies have been published to date on cognitive neurorehabilitation of HAND..."
".....It also remains to be determined whether prophylactic efforts may be made to stave off HAND in at-risk, but neurocognitively normal individuals (see Fig. 2). First, identification of protective factors may help inform protocols for maintenance of cognitive health. One important factor to consider is cognitive reserve, or the combination of innate cognitive ability and life experience to stave off incident neurocognitive impairments associated with aging or neurological disease (Stern 2012). Cognitive reserve has been identified as a protector for neurocognitive impairment (Basso and Bornstein 2000), particularly as it relates to syndromic HAND (Morgan et al. 2012). Using this logic, it is possible that cognitive enrichment and mental activity may delay the development of cognitive impairment (e.g., Treiber et al. 2011) via increased neuroplasticity (Park and Bischof 2011). Outside the scope of cognition-based interventions, a range of lifestyle modifications (e.g., diet high in omega-3 fatty acids; Luchtman and Song 2013) may also help to prevent neurocognitive impairment. One example of such an intervention is the implementation of physical activity regimens, which is theorized to prevent cognitive decline in part through the increased production of neuroprotective factors (e.g., BDNF; Foster et al. 2011). Physical activities as basic as increased walking have yielded positive results on neurocognitive performance in healthy older adults (Jak 2012). If ultimately proven to be effect effective, cognitive and lifestyle interventions such as these may ultimately play a role in HIV standard of care treatment as a prophylaxis for HAND."
"The development, validation, and clinical deployment of efficacious treatments for HAND, including cognitive neuro-rehabilitation approaches, is a clear priority for clinical neuroAIDS investigators. HIV-associated neurocognitive impairments remain prevalent in the cART era and adversely affect a host of everyday activities and HIV health outcomes. Although only a few studies have begun to evaluate the effectiveness of cognitive approaches to treating HAND, their initial results are encouraging, provide important information regarding proof-of-principle, and can directly inform future work. We are aware of a few NIH-funded cognitive rehabilitation studies in neuroAIDS that are presently under way, ranging from training fellowships to Phase I clinical trials."

Despite significant advances in the virologic management of HIV infection over the last two decades, effective treatments for HIV-associated neurocognitive disorders (HAND) remain elusive. While pharmacological interventions have yielded some success in improving neurocognitive outcomes in HIV, there is a dearth of rigorous studies examining the efficacy of cognitive rehabilitation for remediating HIV-associated neurocognitive impairment. This qualitative review summarizes and critiques the emerging literature on cognitive and behavioral treatments for HAND, which provides many reasons for optimism, but also has major limitations that underscore the scope of the work that lies ahead. Considering the notable real-world consequences of HAND, the development, validation, and clinical deployment of cognitive neurorehabilitation interventions tailored to the needs of persons living with HIV infection is a priority for clinical neuroAIDS investigators. In describing potential future directions for this endeavor, particular attention was paid to the application of cognitive neuropsychological principles in developing theory-driven approaches to managing HAND, improving everyday functioning, and enhancing HIV health outcomes.
The first scientific evidence of objective neuropsychological deficits in persons living with HIV infection was published a quarter-century ago (Grant et al. 1987). Subsequent to that seminal study, there has been an abundance of clinical research characterizing the impact of HIV-infection on the brain, including its neuroepidemiology (e.g., incidence and prevalence), neural and cognitive mechanisms, and impact on real world outcomes. However, there has been a paucity of literature dedicated to cognitive and behavioral approaches to treating HIV-associated neurocognitive disorders (HAND). As such, the next challenge for clinical neuroAIDS researchers is to translate the wealth of observational knowledge regarding HAND into effective, theory-driven, and evidence-based treatments that can improve health outcomes in persons living with HIV-infection. In that regard, the aims of this qualitative review are to: 1) briefly review the current state of the HAND literature, including its diagnosis, profile, and effects on everyday functioning; 2) describe current pharmacological management strategies for managing HAND; 3) critically evaluate the limited literature on computerized (and emerging theory-driven) cognitive neurorehabilitation approaches to improving HAND; and 4) outline possible future directions for cognitive rehabilitation research in the context of HIV infection over the next decade.
Clinical Features of HIV-associated Neurocognitive Disorders (HAND)
Diagnosis and Neuroepidemiology of HAND

An important determinant for dedicating scientific resources for the development of an intervention is whether or not the condition of interest is of public health importance (e.g., prevalent and adversely impacts patients, their caregivers, and the healthcare system). HAND occurs in an estimated 30-50 % of individuals with HIV (e.g., Heaton et al. 2010), meaning that approximately 350,000-575,000 persons in the United States alone may suffer from HAND. Annual incidence rates of HAND range from approximately 10 to 25 % (e.g., Robertson et al. 2007). Established risk factors for HAND include older age (e.g., Valcour et al. 2004), lower cognitive reserve (Morgan, Woods, Smith et al. 2012), histories of immune suppression (Ellis et al. 2011), and a host of comorbidities, including substance use disorders (Rippeth et al. 2004) and co-infection with hepatitis C (e.g., Cherner et al. 2005). The updated research nosology for HAND was determined by an NIH working group in Frascati (Antinori et al. 2007), taking into consideration the many clinical and scientific advancements in treatment (i.e., the introduction of combined antiretroviral therapy [cART]) and neuropsychological assessment (e.g., new tests and improved normative standards) of HIV infection, as well as emerging appreciation of important comorbidities (e.g., hepatitis C co-infection). The Frascati criteria allow for three diagnostic categories: Asymptomatic Neuropsychological Impairment (ANI), Mild Neurocognitive Disorder (MND), and HIV-Associated Dementia (HAD) (see Fig. 1). For each of these HAND diagnoses, an individual must demonstrate at least mild neuropsychological impairment (i.e., > 1 SD below the appropriate normative mean) in at least two cognitive domains that is attributable, at least in part, to HIV infection. Meeting this cognitive criterion alone qualifies for a diagnosis of ANI, which comprises approximately 50 % of HAND diagnoses and approximately 15-30 % of cases of HIV infection overall (Grant et al. 2005). ANI has been the most controversial addition to the HAND nosology (Gisslen et al. 2011), as it does not require the presence of functional decline. Dissenting opinions have posited that ANI will cause unnecessary stress for individuals now deemed "neurocognitively impaired" despite no reported symptoms and few viable treatment options (Gisslen et al. 2011). However, Blackstone et al. (2012a) recently demonstrated that many of these "asymptomatic" individuals might actually evidence functional impairment when examined with more sensitive assessment tools (e.g., performance-based everyday functioning tests). Therefore, consideration of ANI diagnoses may be useful in spotlighting individuals who may be unaware of their functional disability (e.g., due to limited insight) or at risk for incident functional decline (Heaton et al. 2012) and may therefore benefit from cognitive neurorehabilitation.
Declines in everyday functioning are central to the diagnostic criteria of both MND and HAD, which necessitate the presence of syndromic, acquired mild-to-moderate (i.e. > 1 SD below the normative mean) or moderate-to-severe (i.e., at least 2 SDs below demographically-adjusted normative means) neurocognitive deficits in 2 or more domains, respectively. The functional dependence criteria for MND are milder than those for HAD and may be determined by evidence of two or more of the following that are not exclusively attributable to a comorbid condition: 1) self- or proxy-report of declines in ≥ 2 instrumental activities of daily living (IADLs; e.g., financial management); 2) unemployment or a significant reduction in job responsibilities secondary to reduced cognitive abilities; 3) decline in vocational functioning (e.g., increased errors, decreased productivity or efficiency); 4) self- or proxy-report of increased problems in ≥ 2 cognitive ability areas in day-to-day life (NB. This criterion can only be used if based in the absence of current depression, which may increase false positive self-reports of complaints); or 5) scores > 1 SD below mean on a performance-based laboratory measure of everyday functioning (e.g., medication management). A diagnosis of HAD requires substantial functional decline, as marked by: 1) unemployment due to cognitive impairment; 2) self- or proxy-report of dependence in > 2 IADLs related to cognitive problems; 3) self- or proxy-report of declines in ≥ 4 cognitive ability areas in day-to-day life (NB. As with a diagnosis of MND, this criterion only applicable if based exclusively on the self-report in the absence of current depression); 4) performance that is > 2 SD below the mean on a performance-based laboratory measure of everyday functioning (or > 1 SD below the mean on two functional tests). MND and HAD are present in approximately 5-20 % and 1-2 % of HIV-infected adults, respectively (Woods et al. 2009a), and represent a significant subpopulation for whom aggressive treatment for neurocognitive impairment is most needed to improve everyday functioning.
Neuropsychological Profile of HAND
In order to identify sensitive and specific targets for prevention and/or remediation of HAND it is essential to first understand its neural mechanisms, affected brain systems, and cognitive architecture (see Fig. 2). HIV is lentivirus that is highly neurotropic, and is able to infiltrate the central nervous system (CNS) through "Trojan Horse" mechanismvia infected monocytes and cluster of differentiation 4 (CD4+) lymphocytes (Hult et al. 2008). Although the virus does not directly infect neurons, it often causes damage to neural tissue through both direct (e.g., viral proteins) and indirect (e.g., inflammatory) processes (Kaul et al. 2001). HIV-associated neuropathology is diverse in the era of cART is characterized by synaptodendric injury and can include HIVencephalitis (HIV-E), vasculopathy, and gliosis (Everall et al. 2009). HIV can affect many different neural pathways, but primarily impacts both the structure (e.g., white matter hyperintensities) and function (e.g., abnormal brain perfusion) of fronto-striatal-thalamocortical (FSTC) circuitry, in addition to medial temporal lobe regions (Thompson et al. 2005).
Consistent with this preferential impact of HIV on
frontostriato-thalamo-cortical neural circuitry (see Ellis et al. 2009), the neurocognitive profile of HAND is often marked by impairments in domains of executive functions, episodic learning and memory, psychomotor speed, and working memory (see Table 1 for tests sensitive to HAND), while deficits in simple attention, sensory perception, receptive language, and visuoperceptual functions are less common. Executive dysfunction is among the most widely studied and well-documented neurocognitive deficits in HIV, particularly in the cART era (e.g., Heaton et al. 2011). Many individuals with HIV evidence deficits on a wide variety of higher-order processes, including abstraction and novel problem solving (e.g., Heaton et al. 1995), cognitive flexibility (e.g., Reger et al. 2002), pre-potent response inhibition (e.g., Martin et al. 2004), and planning (e.g., Cattie et al. 2012). Emergent data also indicate that individuals infected with HIV may be prone to risky decision-making (Hardy et al. 2006), particularly those with HAND (Iudicello et al. 2012), perhaps as a function of cognitive impulsivity (Martin et al. 2004).
The executive aspects of other cognitive ability areas are also frequently affected among persons living with HIV. For instance, the pattern of episodic memory impairment in HAND is most consistent with the prototypical mixed encoding and retrieval profile that is often observed in populations with compromised frontostriatal systems (e.g. Parkinson's disease), with impairment most evident on more executively demanding free recall tasks but normalized performance on more structured recognition trials (Woods et al. 2005). Given the frequently observed pattern of executive dysfunction, learning and memory deficits in HAND are also marked by limited use of higher-order strategic organizational encoding strategies (e.g., Delis et al. 1995), including semantic clustering during list learning (e.g., Gongvatana et al. 2007). Beyond retrospective memory impairment, HIV-infected individuals experience mild-to-moderate impairment on performance-based tests of prospective memory (i.e., "remembering to remember"), marked by a pattern of dysfunctional strategic encoding, monitoring, and retrieval of future intentions (e.g., Carey et al. 2006). Within the broad area of language functioning, HIV is associated with comparably mild-to-moderate impairment on measures of letter and category fluency (Iudicello et al. 2007), thereby suggesting a common mechanism of deficient strategic search and retrieval from lexico-semantic memory stores rather than a degradation of those networks (Woods et al. 2004). The process of switching between lexico-semantic categories during verbal fluency appears to be particularly affected inHAND, especially during alternating fluency trials (Iudicello et al. 2008). Although simple attention (e.g., forward digit span) is generally spared in non-demented persons with HIV infection, deficits on measures of complex attention and working memory are considerably more prevalent (e.g., Heaton et al. 1995; Reger et al. 2002).
Taken together, the neurocognitive profile of HIV infection points toward a primarily dysexecutive syndrome, which may impact various domains of functioning through deficient higher-order strategic abilities (e.g., semantic clustering in verbal learning; Woods et al. 2004) as well as weakened mechanisms for cognitive control (e.g., greater intraindividual variability; Morgan et al. 2011), while sparing relatively less cognitively demanding (e.g., so-called "automatic") processes. Such information about neurocognitive strengths and weaknesses in HIV may be of value in determining both targets (e.g., domains and processes) and approaches (e.g., compensatory aids) for neurorehabilitation of HAND. More specifically, compensatory techniques that aim to capitalize on relatively intact automatic processes (e.g., basic attention, procedural learning) may effectively circumvent relative deficits in strategic neurocognitive processes in order to improve overall functioning (see Fig. 2).
Although a review of the limitations of the HAND literature is beyond the scope of this paper, a few notable gaps in our current knowledge warrant consideration in the context of the burgeoning efforts toward designing effective rehabilitation strategies in HIV. First, we still have only a relatively rudimentary understanding about the natural course o fHAND (i.e., from the acute and early period of HIV infection to death). Needed are prospective, longitudinal studies that can provide reliable estimates of incidence and functional recovery, as well as the predictors, mediators and moderators (e.g., cognitive, demographic, and medical) factors of neurocognitive stability, improvement, and decline (e.g., Mateen et al. 2012). Another fundamental problem is the lack of reliable, sensitive screening tools for clinics to identify HIV-infected individuals for whom treatment for HAND may be indicated (see Valcour et al. 2011).
Everyday Functioning Impact of HAND
Given that HIV-associated neurocognitive deficits are a significant, independent risk factor for a variety of adverse everyday functioning outcomes, developing effective interventions to improve HAND may translate into real world benefits for patients and care providers alike. For instance, neurocognitively impaired HIV+ individuals show deficits across a range of laboratory-based functional tasks compared to their uninfected peers (e.g., cooking, financial and medication management; Heaton et al. 2004). Additionally, HIV-associated neurocognitive impairment is associated with a greater likelihood of being unemployed (Woods et al. 2011), decreases in job-related abilities (Heaton et al. 2004), and difficulties of returning to work after disability (van Gorp et al. 2007). Executive dysfunction (e.g., Hinkin et al. 2002) and impairments in episodicmemory (e.g., Woods et al. 2009b) are reliably associated with lower antiretroviral (ARV) adherence independent of other neuropsychiatric factors and HIV disease severity. HAND (specifically executive dysfunction and visual inattention) is also associated with both simulator and on-road automobile driving difficulties, including a greater number of driving accidents (Marcotte et al. 1999, 2004, 2006). Lastly, greater severity of neurocognitive impairment in HIV infection is independently associated with lower health-related quality of life (Doyle et al. 2012; Tozzi et al. 2004) and higher risk for mortality (Ellis et al. 1997; Wilkie et al. 1998). Given the persistence of HAND in the cART era and its unique role in a wide range of real-world outcomes, the development, validation, and clinical deployment of targeted, effective cognitive neurorehabilitation treatments are needed and of clear importance to health outcomes in HIV disease.
Clinical Course of HAND
The natural history of neuroAIDS suggests that HAND may be responsive to cognitive rehabilitation and that such efforts may yield positive public health gains. Unlike neurodegenerative disorders (e.g., Alzheimer's disease), HAND it is not invariably progressive. In fact, observational longitudinal studies show that it is common for individuals with HAND to remain cognitively stable over time (Cysique, Franklin et al. 2011), and that approximately 21 % may also evidence notable improvements (Robertson et al. 2007). Recognizing the malleability of HAND, the Frascati diagnostic criteria include an "in remission" qualifier for individuals with prior diagnoses of HAND who no longer meet the neurocognitive and/or functional criteria. There are a variety of clinical factors that may relate to the amelioration of neurocognitive deficits, including comorbidity burden (e.g., hepatitis C co-infection), but opportunities for proactive modification of the course of HAND also exist. Such opportunities represent a unique environment for cognitive rehabilitation in the setting of neurological disease, whereby it may be possible to intervene to successfully improve cognition in a relatively young population with a manageable chronic illness. This is especially relevant in the cART era in which persons are now living with HIV infection into their 60s and 70s (CDC 2010). With longer life expectancy and improved health outcomes, it is no longer assumed that HIV-infected individuals will need to collect disability payments as income, but instead, many may seek to continue working until retirement age (van Gorp et al. 2007). It is this prosperous turn in the course of the HIV epidemic that has rendered the need to develop empirically supported methods to improve HAND even more dire.
Cognitive Neurorehabilitation of HAND
The absence of an optimal first-line clinical pharmacotherapy for HAND has led researchers to begin exploring cognitive and behavioral approaches. However, only three studies have been published to date on cognitive neurorehabilitation of HAND. In brief, the vast majority of cognitive rehabilitation approaches across etiologies fall into two categories: restorative and compensatory (see Fig. 2). Restorative approaches rely upon the principle of neuroplasticity and propose that "drill-and-practice" of cognitive skills will encourage more effective neural organization and ultimately improved cognitive abilities (Wykes and Spaulding 2011), based on principles of implicit and procedural learning (Squire 1986). In contrast, compensatory cognitive approaches do not directly aim to correct underlying cognitive deficits, but instead seek to improve cognitive functioning by supporting damaged cognitive processes with both internal (e.g., chunking) or external (e.g., cueing reminders) strategies (Twamley et al. 2003). All three of the HIV studies published thus far adopted a broad restorative approach (i.e., not targeted at a specific cognitive mechanisms) using proprietary computerized rehabilitation tools (e.g., Captain's Log). In this section, we review and critique these three studies, along with a recent series of theorydriven laboratory investigations designed to improve cognition in HIV that might serve to inform future work on rehabilitation of HAND.
SEE ATTACHED PDF to read about the outcomes of these studies

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