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Sensitivity of ventrolateral posterior thalamic nucleus to back pain in alcoholism and CD4 nadir in HIV

Abstract Volumes of thalamic nuclei are differentially affected by disease‐related processes including alcoholism and human immunodeficiency virus (HIV) infection. This MRI study included 41 individuals diagnosed with alcohol use disorders (AUD, 12 women), 17 individuals infected with HIV (eight women), and 49 healthy controls (24 women) aged 39 to 75 years. A specialized, high‐resolution acquisition protocol enabled parcellation of five thalamic nuclei: anterior [anterior ventral (AV)], posterior [pulvinar (Pul)], medial [mediodorsal (MD)], and ventral [including ventral lateral posterior (VLp) and ventral posterior lateral (VPl)]. An omnibus mixed‐model approach solving for volume considered the “fixed effects” of nuclei, diagnosis, and their interaction while covarying for hemisphere, sex, age, and supratentorial volume (svol). The volume by diagnosis interaction term was significant; the effects of hemisphere and sex were negligible. Follow‐up mixed‐model tests thus evaluated the combined (left + right) volume of each nucleus separately for effects of diagnosis while controlling for age and svol. Only the VLp showed diagnoses effects and was smaller in the AUD (p = .04) and HIV (p = .0003) groups relative to the control group. In the AUD group, chronic back pain (p = .008) and impaired deep tendon ankle reflex (p = .0005) were associated with smaller VLp volume. In the HIV group, lower CD4 nadir (p = .008) was associated with smaller VLp volume. These results suggest that the VLp is differentially sensitive to disease processes associated with AUD and HIV.

Individuals with AUD, even without WE or KS typically exhibit cognitive and motor deficits and degradation of specific cortical and subcortical brain regions (Adalsteinsson et al., 2005, May 8-14;Harper, 1998;Parsons & Nixon, 1998). The thalamus is sensitive to uncomplicated (i.e., absent diagnosable neurological complications) alcoholism as manifested by overall volume reduction determined histologically (Kril, Halliday, Svoboda, & Cartwright, 1997). A number of MR imaging studies have confirmed thalamic volume shrinkage in alcoholism (Sullivan et al., 1999;van Holst, de Ruiter, van den Brink, Veltman, & Goudriaan, 2012). An early computerized tomography study in alcoholics suggested that performance on a verbal learning task was associated with reduced density in the region of thalamic MD (Gebhardt, Naeser, & Butters, 1984). By contrast, postmortem histology of the alcoholic brain showed abnormally small neuronal size and reduced neuronal number in anterior thalamic nucleus (Belzunegui, Insausti, Ibanez, & Gonzalo, 1995;Harding et al., 2000).
Another disorder that can result in cognitive compromise and dementia is HIV. HIV-associated neurocognitive disorder (HAND) ranges from asymptomatic to HIV-associated dementia (HAD) (Day et al., 1992;Maj et al., 1994;Nakazato et al., 2014;Robertson et al., 2011). The prevalence of HAD on the severe end of the spectrum has declined with antiretroviral therapy (ART) (Baker et al., 2015;Gates & Cysique, 2016), but mild to moderate cognitive deficits in HIV remain an issue (Manji, Jager, & Winston, 2013;Underwood et al., 2017;Vivithanaporn et al., 2010). Accelerated loss of brain tissue, specifically, in frontal and sensorimotor neocortices, thalamus, and hippocampus-related to disease duration and CD4 nadir (Cohen et al., 2010;Pfefferbaum et al., 2014)-may represent a risk factor for premature cognitive compromise if not dementia (Ances, Ortega, Vaida, Heaps, & Paul, 2012;Pfefferbaum et al., 2014;Pfefferbaum et al., 2018;Sanford et al., 2018). In seeking a neural substrate for HAD, an early imaging study in HIV-infected individuals found no relation between neuropsychological test performance and hippocampal volume (Kieburtz et al., 1996); a later stereological study found no statistically significant differences in hippocampal neuronal number between nine HIV/AIDS patients and 10 controls (Korbo & West, 2000). By contrast, in HIV and alcoholism comorbidity, poor performance on tests of explicit (immediate and delayed) and implicit (visuomotor procedural) memory are associated with smaller thalamic volumes (Fama et al., 2014). Indeed, the thalamus has often been highlighted as a specific target of HIV [volume deficits: Janssen et al., 2015;Pfefferbaum et al., 2012;Pfefferbaum et al., 2014;Pfefferbaum et al., 2018); reduced glucose metabolism: (Hammoud et al., 2018)], possibly related to CD4 count .
A lack of consensus regarding memory substrates in AUD and HIV may be due to limitations related to measuring gross volumes of brain structures. This is exacerbated by lack of reliable and quantitative MRI-based thalamic segmentation schemes. Thalamic nuclei have unique cellular and molecular compositions and distinct connectivity profiles (Poppenk & Moscovitch, 2011) that mirror functional diversity (e.g., Groenewegen & Berendse, 1994;Haber, 2003;Shu, Wu, Bao, & Leonard, 2003) and may account for differential sensitivity to pathological conditions (Byne, Tatusov, Yiannoulos, Vong, & Marcus, 2008;Small, Schobel, Buxton, Witter, & Barnes, 2011). Recently, a method for segmentation of the thalamic nuclei from structural MRI has been proposed that was validated against manual segmentation guided by the Morel atlas . Based on the extant literature, we hypothesized that thalamic nuclei AV and MD would be smaller in AUD and HIV relative to control individuals and relate to performance on tasks of explicit memory (e.g., Pergola et al., 2012;Van der Werf et al., 2003).  Table 1 presents demographic characteristics of the three groups.
All participants were screened with the Structured Clinical Interview for DSM-IV (First, 2000), structured health questionnaires, a semi-structured timeline follow-back interview to quantify lifetime alcohol consumption (Skinner, 1982;Skinner & Allen, 1982), and were given the Clinical Institute Withdrawal Assessment for Alcohol (CIWA). Upon initial assessment, subjects were excluded if they had a significant history of medical (e.g., epilepsy, stroke, multiple sclerosis, uncontrolled diabetes, or loss of consciousness >30 min), psychiatric (i.e., schizophrenia or bipolar I disorder), or neurological disorders (e.g., neurodegenerative disease).
Blood samples (~40 cc) were collected and analyzed by Quest Diagnostics for complete blood count with differential, comprehensive metabolic panel, HIV and HCV screening.
Motor functions evaluated included balance using an ataxia battery (stand heel to toe, walk 10 steps on line, balance on one leg in eyes open and eyes closed conditions) (Fregly, 1968) and upper limb motor function using Grooved Pegboard (Trites, 1977) and Fine Finger Movement . Objective signs of neuropathy (Cornblath et al., 1999;Kaku & Simpson, 2014) (Tourdias, Saranathan, Levesque, Su, & Rutt, 2014). Thalamic nuclear labels were then nonlinearly warped from the atlas space to the input WMn-MPRAGE space and the labels combined using an intelligent joint fusion algorithm to generate one set of thalamic nuclei (Wang et al., 2013).

| MRI acquisition and analysis
Previous work compared the THOMAS segmentation method on data acquired from the same subjects with two different coils (8 vs. 32 channel) (Su, Tourdias, Saranathan, Ghanouni, & Rutt, 2016) and reported comparable performance with no statistical significance in the resulting Dice coefficients relative to manual segmentation. Thus, 8-channel and 32-channel data were combined.
The THOMAS segmentation method, based on data collected at a 7-T field strength, divides the thalamus into 12 nuclei including small structures such as the lateral and medial geniculate nuclei and the centromedian nuclei . Due to lower signal-to-noise and lower contrast at a field strength of 3 T, only the major thalamic analytes, and behavior (e.g., Table 1).
Using a mixed-model approach in JMP, volume was predicted using the "fixed effects" nuclei, diagnosis, and their interaction, while "random effects" included side (i.e., hemisphere), the interaction of side and diagnosis, sex, age, and supratentorial volume (svol). Because a nucleus-by-diagnosis interaction term emerged as significant for this omnibus analysis, follow-up tests considered for each nuclei volume (left + right) the effects of diagnosis while controlling for age and svol.
In the diagnostic groups only, t tests or nonparametric Spearman's ρ evaluated relations between bilateral thalamic nuclei volumes and demographic, clinical, and performance measures.

| Demographics
Although the three groups were well-matched with respect to age, sex, and handedness (Table 1), the two diagnostic groups had lower education, socioeconomic status (SES) (Hollingshead, 1975), estimated premorbid IQ [as per the Wechsler Test of Adult Reading (WTAR), full-scale] (Demakis, Sawyer, Fritz, & Sweet, 2001), and global assessment of functioning (GAF) (Endicott, Spitzer, Fleiss, & Cohen, 1976) than the controls. Individuals in the AUD and HIV groups relative to those in the control group were more likely to be African-American,

| Thalamic nuclei volumes
The mixed model with volume predicted using the "fixed effects" nuclei, diagnosis, and their interaction and the "random effects" side,

| DISCUSSION
Postmortem histology indicates neuronal loss in AV and MD nuclei of brains chronically exposed to alcohol (Belzunegui et al., 1995;Harding et al., 2000). A recent diffusion tensor imaging (DTI) study partially supports these histological findings: probabilistic tractography used to segment the thalamus showed that the MD, which preferentially connects to the prefrontal cortex, is affected by both chronic alcoholism and KS (i.e., untreated thiamine deficiency) while the anterior thalamus, preferentially connected to the hippocampus, is principally affected in KS but not alcoholism per se (Segobin et al., 2019). The current assessment of MR images using semi-automated parcellation of thalamic nuclei did not demonstrate sensitivity of either AV or MD to AUD. Instead, in both AUD and HIV, the thalamic nucleus sensitive to disease was the VLp. That neither AV nor MD was affected may be due to the fact that the alcoholics included in the current study do not suffer from nutritional deficiencies. Inasmuch as acute cross-sectional blood markers can be used to estimate nutrition (e.g., Yildiz & Tufan, 2015), neither the AUD group nor the HIV group was malnourished.
Indeed, the introduction of thiamine enrichment of rice and flour (Axford & Williams, 1981;Bauerfeind, 1988) has significantly reduced the incidence of WE and KS, as reported in Australia (Harper, Fornes, Duyckaerts, Lecomte, & Hauw, 1995). This comports with earlier studies suggesting that only alcoholics with thiamine deficiency have diencephalic damage (Kril et al., 1997;Torvik, 1987;Victor et al., 1989)  The VLp is an integral part of cerebello-thalamocortical (Jones & Pivik, 1985;Kelly & Strick, 2003) and basal ganglia-thalamocortical (Alexander, DeLong, & Strick, 1986;Haber & McFarland, 2001) circuits. In the cerebello-thalamocortical circuit, the VLp receives significant cerebellar afferents (Sakai, Stepniewska, Qi, & Kaas, 2000) and is reciprocally connected with the primary motor area (Stepniewska, Preuss, & Kaas, 1994), the premotor area (Darian-Smith, Darian-Smith, & Cheema, 1990), and the supplementary motor area (SMA) (Sakai et al., 2000). In the basal ganglia-thalamocortical circuit, the VLp is strongly interconnected to the striatum and corresponding cortical areas (Haber & McFarland, 2001;Sakai et al., 2000). In monkeys, VL lesions lead to severe motor dysfunction (Canavan et al., 1989;van Donkelaar, Stein, Passingham, & Miall, 2000). In keeping with evidence that the VL thalamus is a sensorimotor structure also involved in nociception (Dejerine & Roussy, 1906;Garcin & Lapresle, 1954;Head & Holmes, 1911;Schuster, 1937), the current study reports relations between VLp volume, chronic back pain, and impaired ankle reflex in AUD. The relation between chronic back pain and VLp comports with a recent fMRI study suggesting that the magnitude of chronic pain maps to the ventral lateral thalamus (Davis, Ghantous, Farmer, Baria, & Apkarian, 2016). A volume deficit of the VLp may affect sensitivity to pain perception. There is also a precedent for the involvement of the VL thalamus in AUD: Modafinil treatment of AUD patients resulted in improved response inhibition and modulation of brain activity in the VL (Schmaal et al., 2013). Thus, the current results align and contribute to literature supporting VLp as a sensorimotor structure.
In the HIV group, VLp volume selectively correlated with CD4 nadir. Sensitivity of total thalamic volume to CD4 nadir has previously been reported .
A limitation of this study is that three groups were not matched with respect to factors listed in Table 1  While some brain volumetric studies reported significant contributions of such factors to brain integrity (e.g., Garcia-Garcia et al., 2019;Holz, Laucht, & Meyer-Lindenberg, 2015;Kesler, Adams, Blasey, & Bigler, 2003), the current study did not find relations between variables differing among the three groups listed in Table 1  F I G U R E 3 VLp relations. (a) In the AUD group, smaller VLp volume correlated with self-report of chronic back pain the past year and impaired deep tendon ankle reflex. (b) In the HIV group, smaller VLp volume correlated with lower CD4 nadir 2018) groups relative to healthy controls did not find significant contributions of such factors to global brain integrity.
To our knowledge, this is the first volumetric study of thalamic nuclei volumes in AUD or HIV. It was expected that AUD and HIV would differentially affect volumes of unique thalamic nuclei (cf., Byne et al., 2008;Small et al., 2011); instead, both conditions were associated with smaller VLp volume. This finding is in contrast to results in multiple sclerosis that appears to specifically target AV and Pul thalamic nuclei (Planche et al., 2019). Whether AUD or HIV directly or indirectly contribute to VLp volume compromise cannot be determined by the current study. While unlikely that nutritional factors contributed to volume decline in either condition, a low CD4 cell count may selectively target the thalamus in HIV .
In conclusion, the current report indicates that VLp volume is sensitive to both AUD and HIV and is related to chronic back pain in AUD and to CD4 nadir in HIV.

ACKNOWLEDGMENTS
This study was supported with grant funding from the National Institute of Alcohol Abuse and Alcoholism (NIAAA): R21 AA023582, R01 AA005965, U01 AA017347, R37 AA010723, and National Institute of Mental Health: R01 MH113406.

CONFLICT OF INTEREST
The authors declare no potential conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study will be openly available at an online data repository such as https://datadryad.org/.