Viral Load Dynamics in Plasma and Semen When Antiretroviral Therapy Is Initiated During Early HIV-1 Infection.

We assessed human immunodeficiency virus (HIV) load in plasma and semen during primary HIV infection using serial samples of semen and plasma during the first 24 weeks after diagnosis in untreated participants and those who started antiretroviral therapy (ART) immediately at diagnosis. In the absence of treatment, semen viral load was >1000 copies/mL in almost all specimens (83%) collected 2-10 weeks after the estimated date of HIV acquisition and remained >1000 copies/mL in 35% of untreated participants at the last observed time point. Thus, in the absence of ART, semen viral load remained at a level consistent with transmissibility throughout primary infection.

Linkage to care after HIV diagnosis among men who have sex with men and transgender women in Lima, Peru.

In Lima, Perú, HIV prevalence is estimated to be 15% among men who have sex with men (MSM) and 30% among transgender women (TW). We investigated timely linkage of MSM and TW to HIV care, as linkage to antiretroviral therapy (ART) is critical to protect the health of those living with HIV and to prevent onward transmission. We investigated linkage within 90 days of HIV diagnosis by matching data from two studies conducted in Lima between 2013 and 2015 to national ART program records. We used generalized linear modeling to assess predictors of timely linkage and late presentation to care. Of 487 newly-diagnosed MSM and TW, only 44% presented for care at an HIV clinic within 90 days. Timely linkage was less common among TW (aPR 0.7, 95% CI 0.5-1.0), those younger than 24 (aPR 0.8, 95% CI 0.6-1.0), and those reporting a history of sex work (aPR 0.7, 95% CI 0.6-0.9). Proximity to an ART program clinic was not associated with linkage; most participants linked to clinics offering "LGBTQ-friendly" care. The pattern of clinics selected by participants suggests the importance of concerns about confidentiality and stigma in decision-making about where to link to care.

Persistence of oral pre-exposure prophylaxis (PrEP) among adolescent girls and young women initiating PrEP for HIV prevention in Kenya.

The Determined, Resilient, Empowered, AIDS-free, Mentored, and Safe (DREAMS) Initiative aims to reduce HIV infections among adolescent girls and young women (AGYW) in Africa. Oral pre-exposure prophylaxis (PrEP) is offered through DREAMS in Kenya to eligible AGYW in high burden counties including Kisumu and Homa Bay. This study examines PrEP persistence among AGYW in high burden community-based PrEP delivery settings. We evaluated PrEP persistence among AGYW in the DREAMS PrEP program in Kisumu and Homa Bay using survival analysis and programmatic PrEP refill data collected between March through December 2017. Among 1,259 AGYW who initiated PrEP during the study period, the median persistence time in the program was 56 days (95% CI: 49-58 days) and the proportion who persisted 3 months later was 37% (95% CI: 34-40%). Persistence varied by county (p < 0.001), age at PrEP initiation (p = 0.002), marital status (p = 0.008), transactional sex (p = 0.002), gender-based violence (GBV) experience (p = 0.009) and current school attendance (p = 0.001) at DREAMS enrollment. Persistence did not vary with orphan status, food insecurity, condom use, age at first sexual encounter or engagement in age-disparate sex at DREAMS enrollment. Targeted strategies are needed to improve AGYW retention in the PrEP program.

Skin and Soft Tissue Infection in People Living With Human Immunodeficiency Virus in a Large, Urban, Public Healthcare System in Houston, Texas, 2009-2014.

BACKGROUND: Skin and soft tissue infections (SSTIs) disproportionately impact patients with human immunodeficiency virus (HIV). Recent declines in the incidence of SSTIs have been noted in the non-HIV population. We sought to study the epidemiology and microbiology of SSTIs in a population of 8597 patients followed for HIV primary care in a large, urban county system from January 2009 to December 2014. METHODS: SSTIs were identified from the electronic medical record by use of International Classification of Diseases-9 billing codes. Charts were reviewed to confirm each patient's diagnosis of acute SSTI and abstract culture and susceptibility data. We calculated the yearly SSTI incidences using Poisson regression with clustering by patient. RESULTS: There were 2202 SSTIs identified. Of 503 (22.8%) cultured SSTIs, 332 (66.0%) recovered Staphylococcus aureus as a pathogen, of which 287/332 (86.4%) featured S. aureus as the sole isolated organism. Among the S. aureus isolates that exhibited antibiotic susceptibilities, 231/331 (69.8%) were methicillin resistant, and the proportion did not change by year. The observed incidence of SSTI was 78.0 per 1000 person-years (95% confidence interval 72.9-83.4) and declined from 96.0 infections per 1000 person-years in 2009 to 56.5 infections per 1000 person-years in 2014 (P < .001). Other significant predictors of SSTI incidences in both univariate as well as multivariate analyses included a low CD4 count, high viral load, and not being a Spanish-speaking Hispanic. CONCLUSIONS: SSTIs remain a significant problem in the outpatients living with HIV, although rates of SSTIs appear to have declined by approximately 40% between 2009 and 2014.

Correction to: Experienced HIV-Related Stigma and Psychological Distress in Peruvian Sexual and Gender Minorities: A Longitudinal Study to Explore Mediating Roles of Internalized HIV-Related Stigma and Coping Styles.

Correction to: AIDS and Behavior (2018) 1-14 https://doi.org/10.1007/s10461-018-2348-2 . In the original publication of the article, the given name of the second author was not correct. The name has been corrected with this erratum.

Experienced HIV-Related Stigma and Psychological Distress in Peruvian Sexual and Gender Minorities: A Longitudinal Study to Explore Mediating Roles of Internalized HIV-Related Stigma and Coping Styles.

Experiencing HIV-related stigma has important impacts on the mental health of people living with HIV, which has implications for treatment adherence, disease progression, and health outcomes. The impacts of stigma are particularly important to consider among sexual and gender minorities, who often face a disproportionate burden of HIV. To address the implications of stigma in these key populations, we leveraged a longitudinal study conducted among Peruvian sexual and gender minorities to compare the relative effects of multiple mediators affecting the relationship between experienced HIV-related stigma and psychological distress: internalized HIV-related stigma, adaptive coping, and maladaptive coping. HIV-related stigma, coping, and distress were measured, respectively, at 24 weeks, 36 weeks, and 48 weeks post-diagnosis for 145 participants from the Sabes Study. HIV-related maladaptive coping largely mediated the relationship between experienced HIV-related stigma and distress. Our findings suggest interventions targeting maladaptive coping may alleviate the mental health consequences of experiencing HIV-related stigma.

Impact of pre-diagnosis awareness of HIV-related stigma and dispositional coping on linkage to HIV care among newly diagnosed HIV+ Peruvian patients.

A substantial body of literature has characterized how psychosocial factors, including HIV-related stigma and coping, are associated with HIV testing and HIV care utilization post-diagnosis. Less is known about if certain psychosocial characteristics pre-diagnosis may also predict linkage to care among individuals who receive an HIV-positive diagnosis. We examined if pre-diagnosis awareness/perception about HIV-related stigma and dispositional coping styles predicted linkage to HIV care within three months post-diagnosis with a secondary analysis of 604 patients from a randomized controlled trial (Sabes Study). Awareness/perception about HIV-related stigma, dispositional maladaptive and adaptive coping were measured before patients underwent an HIV test. Linkage to care was measured as receipt of care within three months of receiving the diagnosis. After adjusting for covariates, individuals who reported greater dispositional maladaptive coping pre-diagnosis had lower odds of linking to care, OR = 0.82, 95%CI [0.67, 1.00], p = .05. There was also a non-significant inverse association between dispositional adaptive coping pre-diagnosis and linkage to care. These preliminary data suggest the need for further longitudinal research and highlight the potential utility of pre-diagnosis psychosocial assessment and tailored counseling when providing positive HIV diagnosis results.

Acute HIV Discovered During Routine HIV Screening With HIV Antigen-Antibody Combination Tests in 9 US Emergency Departments.

STUDY OBJECTIVE: Newer combination HIV antigen-antibody tests allow detection of HIV sooner after infection than previous antibody-only immunoassays because, in addition to HIV-1 and -2 antibodies, they detect the HIV-1 p24 antigen, which appears before antibodies develop. We determine the yield of screening with HIV antigen-antibody tests and clinical presentations for new diagnoses of acute and established HIV infection across US emergency departments (EDs). METHODS: This was a retrospective study of 9 EDs in 6 cities with HIV screening programs that integrated laboratory-based antigen-antibody tests between November 1, 2012, and December 31, 2015. Unique patients with newly diagnosed HIV infection were identified and classified as having either acute HIV infection or established HIV infection. Acute HIV infection was defined as a repeatedly reactive antigen-antibody test result, a negative HIV-1/HIV-2 antibody differentiation assay, or Western blot result, but detectable HIV ribonucleic acid (RNA); established HIV infection was defined as a repeatedly reactive antigen-antibody test result and a positive HIV-1/HIV-2 antibody differentiation assay or Western blot result. The primary outcomes were the number of new HIV diagnoses and proportion of patients with laboratory-defined acute HIV infection. Secondary outcomes compared reason for visit and the clinical presentation of acute HIV infection. RESULTS: In total, 214,524 patients were screened for HIV and 839 (0.4%) received a new diagnosis, of which 122 (14.5%) were acute HIV infection and 717 (85.5%) were established HIV infection. Compared with patients with established HIV infection, those with acute HIV infection were younger, had higher RNA and CD4 counts, and were more likely to have viral syndrome (41.8% versus 6.5%) or fever (14.3% versus 3.4%) as their reason for visit. Most patients with acute HIV infection displayed symptoms attributable to acute infection (median symptom count 5 [interquartile range 3 to 6]), with fever often accompanied by greater than or equal to 3 other symptoms (60.7%). CONCLUSION: ED screening using antigen-antibody tests identifies previously undiagnosed HIV infection at proportions that exceed the Centers for Disease Control and Prevention's screening threshold, with the added yield of identifying acute HIV infection in approximately 15% of patients with a new diagnosis. Patients with acute HIV infection often seek ED care for symptoms related to seroconversion.

Unintended adverse consequences of electronic health record introduction to a mature universal HIV screening program.

Early HIV detection and treatment decreases morbidity and mortality and reduces high-risk behaviors. Many Emergency Departments (EDs) have HIV screening programs as recommended by the Centers for Disease Control and Prevention. Recent federal legislation includes incentives for electronic health record (EHR) adoption. Our objective was to analyze the impact of conversion to EHR on a mature ED-based HIV screening program. A retrospective pre- and post-EHR implementation cohort study was conducted in a large urban, academic ED. Medical records were reviewed for HIV screening rates from August 2008 through October 2013. On 1 November 2010, a comprehensive EHR system was implemented throughout the hospital. Before EHR implementation, labs were requested by providers by paper orders with HIV-1/2 automatically pre-selected on every form. This universal ordering protocol was not duplicated in the new EHR; rather it required a provider to manually enter the order. Using a chi-squared test, we compared HIV testing in the 6 months before and after EHR implementation; 55,054 patients presented before, and 50,576 after EHR implementation. Age, sex, race, acuity of presenting condition, and HIV seropositivity rates were similar pre- and post-EHR, and there were no major patient or provider changes during this period. Average HIV testing rate was 37.7% of all ED patients pre-, and 22.3% post-EHR, a 41% decline (p < 0.0001), leading to 167 missed new diagnoses after EHR. The rate of HIV screening in the ED decreased after EHR implementation, and could have been improved with more thoughtful inclusion of existing human processes in its design.

Acute retroviral syndrome is associated with lower CD4 + T cell nadir and delayed viral suppression, which are blunted by immediate antiretroviral therapy initiation.

OBJECTIVES: To describe the prevalence of acute retroviral syndrome (ARS) and associated findings during primary HIV, and explore the relationship of ARS to clinical, virological, and immunological outcomes within a longitudinal screen, retest and treat study that minimized ascertainment bias. DESIGN: We evaluated ARS symptoms and signs among 216 persons with acute and early incident HIV within the Sabes study of timing of antiretroviral therapy (ART) initiation during primary HIV in Peru. METHODS: We evaluated patient reported symptoms and signs during primary HIV and used logistic regression and generalized linear models to evaluate associations with CD4 + and CD8 + T cell counts, HIV viral load, and a panel of 23 soluble markers of immune activation. RESULTS: Sixty-one percent of participants had at least one ARS finding and 35% had at least 3. More ARS findings were reported in those enrolled within a month of estimated date of detectable infection (EDDI). Having more ARS signs/symptoms was associated with increased risk of CD4 + cell decrease below 350 cells/ml within the first 24 weeks, failure to suppress HIV viral load, and was most strongly associated with elevated IP-10. Immediate ART blunted effects on symptoms, CD4 + cell count and viral load, as associations were strongest in the arm that started ART after 24 weeks. Detrimental associations of ARS with CD4 + counts, and CD4 + /CD8 + ratio were not maintained at 2 or 4 years. CONCLUSIONS: ARS has marked associations with short-term immunologic function and virologic suppression, which were mitigated in participants randomized to initiate ART immediately during primary infection.

Dynamic immune markers predict HIV acquisition and augment associations with sociobehavioral factors for HIV exposure.

Prior studies attempting to link biomarkers of immune activation with risk of acquiring HIV have relied on cross sectional samples, most without proximity to HIV acquisition. We created a nested case-control study within the Sabes study in Peru, and assessed a panel of plasma immune biomarkers at enrollment and longitudinally, including within a month of diagnosis of primary HIV or matched timepoint in controls. We used machine learning to select biomarkers and sociobehavioral covariates predictive of HIV acquisition. Most biomarkers were indistinguishable between cases and controls one month before HIV diagnosis. However, levels differed between cases and controls at study entry, months to years earlier. Dynamic changes in IL-2, IL-7, IL-10, IP-10 and IL-12, rather than absolute levels, jointly predicted HIV risk when added to traditional risk factors, and there was modest effect modification of biomarkers on association between sociobehavioral risk factors and HIV acquisition.

Immune Activation in Primary Human Immunodeficiency Virus: Influence of Duration of Infection, Treatment, and Substance Use.

Background: Primary human immunodeficiency virus (HIV) is characterized by dynamic changes in viral load and innate and adaptive immune responses; it is unclear the extent to which time from acquisition to antiretroviral therapy (ART) initiation and substance use impact these immunologic changes. Methods: We studied plasma immune activation biomarkers, viral load, and CD4+ and CD8+ cell counts in participants from the Sabes primary infection study in Peru, who had been randomized to begin ART immediately after diagnosis vs 24 weeks later. We modeled influence of substance use and duration of HIV infection on biomarkers at baseline and over 24 weeks. Results: Compared to participants enrolled >30 days after HIV acquisition, participants enrolled during acute infection (≤30 days) had higher mean interferon (IFN)-γ and IFN-α2a (1.7-fold and 3.8-fold interquartile range [IQR] higher, respectively). Participants enrolled >30 days after HIV acquisition had higher mean baseline CD8+ cell count (2.7 times the IQR). Alcohol use (positive phosphatidylethanol level) was associated with elevated IFN-γ, tumor necrosis factor alpha (TNF-α), and interleukin 12p70 (IL-12p70), and smoking was associated with higher macrophage inflammatory protein 1α, TNF-α, and IL-12p70. Most biomarkers declined more quickly in participants who initiated ART immediately; however, substance use and duration of HIV infection at enrollment had little influence on rate of decline. Conclusions: IFN-γ and other biomarkers are elevated during early primary infection, when exposure to HIV antigens is high. Immune activation decreased most quickly in those who started ART during acute/early primary infection. Higher CD8+ cell counts and a trend toward higher soluble CD163 levels during the 30 days after acquisition suggest the onset of compensatory responses and immune exhaustion.

HIV Disease Dynamics and Markers of Inflammation and CNS Injury During Primary HIV Infection and Their Relationship to Cognitive Performance.

INTRODUCTION: Early systemic and central nervous system viral replication and inflammation may affect brain integrity in people with HIV, leading to chronic cognitive symptoms not fully reversed by antiretroviral therapy (ART). This study examined associations between cognitive performance and markers of CNS injury associated with acute HIV infection and ART. METHODS: HIV-infected MSM and transgender women (average age: 27 years and education: 13 years) enrolled within 100 days from the estimated date of detectable infection (EDDI). A cognitive performance (NP) protocol was administered at enrollment (before ART initiation) and every 24 weeks until week 192. An overall index of cognitive performance (NPZ) was created using local normative data. Blood (n = 87) and cerebrospinal fluid (CSF; n = 29) biomarkers of inflammation and neuronal injury were examined before ART initiation. Regression analyses assessed relationships between time since EDDI, pre-ART biomarkers, and NPZ. RESULTS: Adjusting for multiple comparisons, shorter time since EDDI was associated with higher pre-ART VL and multiple biomarkers in plasma and CSF. NPZ scores were within the normative range at baseline (NPZ = 0.52) and at each follow-up visit, with a modest increase through week 192. Plasma or CSF biomarkers were not correlated with NP scores at baseline or after ART. CONCLUSIONS: Biomarkers of CNS inflammation, immune activation, and neuronal injury peak early and then decline during acute HIV infection, confirming and extending results of other studies. Neither plasma nor CSF biomarkers during acute infection corresponded to NP scores before or after sustained ART in this cohort with few psychosocial risk factors for cognitive impairment.

fMRI-Guided transcranial magnetic stimulation reveals that the superior temporal sulcus is a cortical locus of the McGurk effect.

A compelling example of auditory-visual multisensory integration is the McGurk effect, in which an auditory syllable is perceived very differently depending on whether it is accompanied by a visual movie of a speaker pronouncing the same syllable or a different, incongruent syllable. Anatomical and physiological studies in human and nonhuman primates have suggested that the superior temporal sulcus (STS) is involved in auditory-visual integration for both speech and nonspeech stimuli. We hypothesized that the STS plays a critical role in the creation of the McGurk percept. Because the location of multisensory integration in the STS varies from subject to subject, the location of auditory-visual speech processing in the STS was first identified in each subject with fMRI. Then, activity in this region of the STS was disrupted with single-pulse transcranial magnetic stimulation (TMS) as subjects rated their percept of McGurk and non-McGurk stimuli. Across three experiments, TMS of the STS significantly reduced the likelihood of the McGurk percept but did not interfere with perception of non-McGurk stimuli. TMS of the STS was effective at disrupting the McGurk effect only in a narrow temporal window from 100 ms before auditory syllable onset to 100 ms after onset, and TMS of a control location did not influence perception of McGurk or control stimuli. These results demonstrate that the STS plays a critical role in the McGurk effect and auditory-visual integration of speech.

Representation of limb kinematics in Purkinje cell simple spike discharge is conserved across multiple tasks.

Encoding of movement kinematics in Purkinje cell simple spike discharge has important implications for hypotheses of cerebellar cortical function. Several outstanding questions remain regarding representation of these kinematic signals. It is uncertain whether kinematic encoding occurs in unpredictable, feedback-dependent tasks or kinematic signals are conserved across tasks. Additionally, there is a need to understand the signals encoded in the instantaneous discharge of single cells without averaging across trials or time. To address these questions, this study recorded Purkinje cell firing in monkeys trained to perform a manual random tracking task in addition to circular tracking and center-out reach. Random tracking provides for extensive coverage of kinematic workspaces. Direction and speed errors are significantly greater during random than circular tracking. Cross-correlation analyses comparing hand and target velocity profiles show that hand velocity lags target velocity during random tracking. Correlations between simple spike firing from 120 Purkinje cells and hand position, velocity, and speed were evaluated with linear regression models including a time constant, τ, as a measure of the firing lead/lag relative to the kinematic parameters. Across the population, velocity accounts for the majority of simple spike firing variability (63 ± 30% of R(adj)(2)), followed by position (28 ± 24% of R(adj)(2)) and speed (11 ± 19% of R(adj)(2)). Simple spike firing often leads hand kinematics. Comparison of regression models based on averaged vs. nonaveraged firing and kinematics reveals lower R(adj)(2) values for nonaveraged data; however, regression coefficients and τ values are highly similar. Finally, for most cells, model coefficients generated from random tracking accurately estimate simple spike firing in either circular tracking or center-out reach. These findings imply that the cerebellum controls movement kinematics, consistent with a forward internal model that predicts upcoming limb kinematics.

Sexual Behavior Among Men Who Have Sex With Men: The Need for More Targeted Outreach to Men Who Also Have Sex With Cisgender Women.

BACKGROUND: In Peru, as in the Americas overall, men who have sex with men (MSM) are disproportionately affected by HIV. Most research focuses on practices between cisgender men, whereas many MSM report male and female partners, cisgender, transgender, or both. METHODS: Data for these analyses were from a treatment-as-prevention study in Lima (the Sabes study). We compared demographics and behaviors of MSM who reported cisgender women partners in the past 3 months (MSMW) and MSM who reported both cisgender and transgender women partners (MSMW-T) to MSM who reported only male partners (MSMO). We calculated HIV incidence in each group during 2-year follow-up. RESULTS: Compared with MSMO, MSMW and MSMW-T more often self-identify as heterosexual or bisexual and report insertive sex practices. MSMW reported condomless sex with cisgender women: vaginal (72%), anal sex (18%). One-third of MSMW reported condomless receptive anal sex with men in the past 3 months, with 24% of MSMW overall who reported both condomless receptive sex with men and condomless insertive vaginal or anal sex with cisgender women. Of these, 17% were HIV infected. HIV incidence did not differ significantly between groups. CONCLUSION: Most MSMW and MSMW-T report bisexual or heterosexual orientation and prefer insertive sex. MSMW and MSMW-T (47% and 29%, respectively) engage in receptive anal intercourse. In both groups, the majority who engaged in condomless receptive sex with men (76% MSMW, 85% MSMW-T) also engaged in condomless vaginal and/or anal sex with women, indicating need for intervention.

TMS of posterior parietal cortex disrupts visual tactile multisensory integration.

Functional neuroimaging studies have implicated a number of brain regions, especially the posterior parietal cortex (PPC), as being potentially important for visual-tactile multisensory integration. However, neuroimaging studies are correlational and do not prove the necessity of a region for the behavioral improvements that are the hallmark of multisensory integration. To remedy this knowledge gap, we interrupted activity in the PPC, near the junction of the anterior intraparietal sulcus and the postcentral sulcus, using MRI-guided transcranial magnetic stimulation (TMS) while subjects localized touches delivered to different fingers. As the touches were delivered, subjects viewed a congruent touch video, an incongruent touch video, or no video. Without TMS, a strong effect of multisensory integration was observed, with significantly better behavioral performance for discrimination of congruent multisensory touch than for unisensory touch alone. Incongruent multisensory touch produced a smaller improvement in behavioral performance. TMS of the PPC eliminated the behavioral advantage of both congruent and incongruent multisensory stimuli, reducing performance to unisensory levels. These results demonstrate a causal role for the PPC in visual-tactile multisensory integration. Taken together with converging evidence from other studies, these results support a model in which the PPC contains a map of space around the hand that receives input from both the visual and somatosensory modalities. Activity in this map is likely to be the neural substrate for visual-tactile multisensory integration.

The role of left vs. right superior temporal gyrus in speech perception: An fMRI-guided TMS study.

Debate continues regarding the necessary role of right superior temporal gyrus (STG) regions in sublexical speech perception given the bilateral STG activation often observed in fMRI studies. To evaluate the causal roles, TMS pulses were delivered to inhibit and disrupt neuronal activity at the left and right STG regions during a nonword discrimination task based on peak activations from a blocked fMRI paradigm assessing speech vs. nonspeech perception (N = 20). Relative to a control region located in the posterior occipital lobe, TMS to the left anterior STG (laSTG) led to significantly worse accuracy, whereas TMS to the left posterior STG (lpSTG) and right anterior STG (raSTG) did not. Although the disruption from TMS was significantly greater for the laSTG than for raSTG, the difference in accuracy between the laSTG and lpSTG did not reach significance. The results argue for a causal role of the laSTG but not raSTG in speech perception. Further research is needed to establish the source of the differences between the laSTG and lpSTG.

Cerebellum predicts the future motor state.

Feed forward control and estimates of the future state of the motor system are critical for fast and coordinated movements. One framework for generating these predictive signals is based on the central nervous system implementing internal models. Internal models provide for representations of the input-output properties of the motor apparatus or their inverses. It has been widely hypothesized that the cerebellum acquires and stores internal models of the motor apparatus. The results of psychophysical, functional imaging and transcranial magnetic stimulation studies in normal subjects support this hypothesis. Also, the deficits in patients with cerebellar dysfunction can be attributed to a failure of predictive feed forward control and/or to accurately estimate the consequences of motor commands. Furthermore, the computation performed by the cerebellar-like electrosensory lobes in several groups of fishes is to predict the sensory consequences of motor commands. However, only a few electrophysiological investigations have directly tested whether neurons in the cerebellar cortex have the requisite signals compatible with either an inverse or forward internal model. Our studies in the monkey performing manual pursuit tracking demonstrate that the simple spike discharge of Purkinje cells does not have the dynamics-related signals required to be the output of an inverse dynamics model. However, Purkinje cell firing has several of the characteristics of a forward internal model of the arm. A synthesis of the evidence suggests that the cerebellum is involved in integrating the current state of the motor system with internally generated motor commands to predict the future state.

Position, direction of movement, and speed tuning of cerebellar Purkinje cells during circular manual tracking in monkey.

The cerebellum plays an essential role in pursuit tracking with the eye and with the hand. During smooth pursuit eye movements, both tracking position and velocity are signaled by Purkinje cells. Purkinje cell simple spike discharge is also modulated by direction and speed during linear manual tracking. This study evaluated how all three parameters, position, movement direction, and speed, are signaled in the simple spike discharge of Purkinje cells during circular manual tracking. Three rhesus monkeys intercepted and then tracked a target moving in a circle in both counterclockwise and clockwise directions across a range of constant target speeds. Two sets of analyses of the simple spike firing of 97 Purkinje cells examined the effects of position, movement direction, and speed. The first approach was the incremental improvement of regression models, initially modeling a pure position dependence, then incorporating movement direction, and finally incorporating speed dependence. The second was a model-independent approach, without any explicit assumptions about the character of the directional tuning or speed effects. Both analyses revealed the same three results: (1) Purkinje cell discharge is spatially tuned, to both the position and direction of movement, and (2) this spatial tuning is not altered by the speed, except (3) the speed scales the average firing and/or depth of modulation. The results suggest that the population of Purkinje cells forms a representation of the entire position-direction space of arm movements, and that the speed modulates the scale of that representation. This speed scaling provides insights into the cerebellar processing of movement-related timing.