The cognitive modulation of pain is influenced by a number of factors ranging from attention, beliefs, conditioning, expectations, mood, and the regulation of emotional responses to noxious sensory events. Recently, mindfulness meditation has been found attenuate pain through some of these mechanisms including enhanced cognitive and emotional control, as well as altering the contextual evaluation of sensory events. This review discusses the brain mechanisms involved in mindfulness meditation-related pain relief across different meditative techniques, expertise and training levels, experimental procedures, and neuroimaging methodologies. Converging lines of neuroimaging evidence reveal that mindfulness meditation-related pain relief is associated with unique appraisal cognitive processes depending on expertise level and meditation tradition. Moreover, it is postulated that mindfulness meditation-related pain relief may share a common final pathway with other cognitive techniques in the modulation of pain.

Objective Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease (PD) clinical trials raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 PET tracers with in vitro measures of nigral cell counts and striatal dopamine in MPTP treated monkeys. Methods Sixteen macaques had MRI and baseline PETs using 6-[18F]fluorodopa (FD), [11C] dihydrotetrabenazine (DTBZ) and [11C] 2beta-carbomethoxy-3beta-4-fluorophenyltropane (CFT). MPTP (0 to 0.31 mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by three weeks. After eight weeks, PETs were repeated and animals euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylase stained nigral cells. Results Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss < 50% (r2= 0.84; r2= 0.86; r2= 0.87, p<0.001 respectively; n=10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2= 0.95; r2= 0.94; r2= 0.94, p<0.001; n=16). Interestingly, indices of striatal uptake of FD, DTBZ and CFT correlated strongly with each other (r2=0.98, p<0.001). Interpretation Tracer uptake correlated with nigral neurons only when nigral loss < 50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury.

Objective Nigrostriatal reserve refers to the threshold of neuronal injury to dopaminergic cell bodies and their terminal fields required to produce parkinsonian motor deficits. Inferential studies have estimated striatal dopamine reserve to be at least 70%. Knowledge of this threshold is critical for planning interventions to prevent symptom onset or reverse nigrostriatal injury sufficient to restore function in people with Parkinson disease. In this study, we determine the nigrostriatal reserve in a non-human primate model that mimics the motor manifestations of Parkinson disease. Methods Fifteen macaque monkeys received unilateral randomized doses of the selective dopaminergic neuronal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We compared blinded validated ratings of parkinsonism to in vitro measures of striatal dopamine and unbiased stereologic counts of nigral neurons after tyrosine hydroxylase immunostaining. Results The percent of residual cell counts in lesioned nigra correlated linearly with the parkinsonism score at 2 months (r = −0.87, p <0.0001). The parkinsonism score at 2 months correlated linearly with the percent residual striatal dopamine (r = −0.77, p = 0.016) followed by a flooring effect once nigral cell loss exceeded 50%. A reduction of about 14 to 23% of nigral neuron counts or 14 to 37% of striatal dopamine was sufficient to induce mild parkinsonism. Conclusions The nigral cell body and terminal field injury needed to produce parkinsonian motor manifestations may be much less than previously thought.

We explored whether white matter (WM) integrity in cognitively normal (CN) older adults is associated with cerebrospinal fluid (CSF) markers of Alzheimer’s disease (AD) pathology. Twenty CN older adults underwent lumbar puncture and magnetic resonance imaging within a few days of each other. Analysis of diffusion tensor imaging data involved a priori region of interest (ROI) and voxelwise approaches. The ROI results revealed a positive correlation between CSF measures of amyloid-beta (Aβ42 and Aβ42/p-Tau181) and WM integrity in the fornix, a relationship which persisted after controlling for hippocampal volume and fornix volume. Lower WM integrity in the same portion of the fornix was also associated with reduced performance on the Digit Symbol test. Subsequent exploratory voxelwise analyses indicated a positive correlation between CSF Aβ42/p-Tau181 and WM integrity in bilateral portions of the fornix, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, and in the corpus callosum and left inferior longitudinal fasciculus. Our results link lower WM microstructural integrity in CN older adults with CSF biomarkers of AD and suggest that this association in the fornix may be independent of volumetric measures.

Apathy, primarily defined as a lack of motivation, commonly occurs in people with Parkinson disease (PD). Although dysfunction of basal ganglia pathways may contribute to apathy, the role of dopamine remains largely unknown. We investigated the role of dopaminergic pathways in the manifestation of apathetic behaviors by measuring the effects of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on monkeys’ willingness to attempt goal directed behaviors, distinct from their ability to perform tasks. Fifteen macaques received variable doses of MPTP, had PET scans with [11C]-dihydrotetrabenazine (DTBZ), [11C]-2β-3β-4-fluorophenyltropane (CFT), and [18F]-fluorodopa (FD) and performed tasks to assess apathetic behaviors and motor impairment. At 8 weeks post-MPTP, primates were euthanized and stereological cell counts and dopamine measurements were done. Apathy scores were compared to motor scores, in vitro and in vivo dopaminergic measures. Apathy scores increased following MPTP and correlated with DTBZ (rS = −0.85), CFT (rS = −0.87), and FD (rS = −0.85) specific uptake in nucleus accumbens (NAcc,) and dopaminergic cell counts in ventral tegmental area (VTA, rS = −0.80). Dopaminergic cell loss in VTA provided significant predictive power for apathy scores after controlling for the influence of cell loss in SN. Additionally, forward step-wise regression analyses indicated that neuropathological changes in the VTA-NAcc pathway predict apathetic behavior better than motor impairment or neuropathological changes in the nigrostriatal network. Our findings suggest that dopaminergic dysfunction within the VTA-NAcc pathway plays a role in the manifestation of apathetic behaviors in MPTP-lesioned primates. Similar changes in people with PD may contribute to apathy.

Radioligands for DAT and VMAT2 are widely used presynaptic markers for assessing dopamine (DA) nerve terminals in Parkinson disease (PD). Previous in vivo imaging and postmortem studies suggest that these transporter sites may be regulated as the numbers of nigrostriatal neurons change in pathologic conditions. To investigate this issue, we used in vitro quantitative autoradioradiography to measure striatal DAT and VMAT2 specific binding in postmortem brain from 14 monkeys after unilateral internal carotid artery infusion of 1-Methyl-4-Phenyl-1,2,3,6-tetrahydropyridine (MPTP) with doses varying from 0 to 0.31 mg/kg. Quantitative estimates of the number of tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in substantia nigra (SN) were determined with unbiased stereology, and quantitative autoradiography was used to measure DAT and VMAT2 striatal specific binding. Striatal VMAT2 and DAT binding correlated with striatal DA (rs = 0.83, rs = 0.80, respectively, both with n = 14, p<0.001) but only with nigra TH-ir cells when nigral cell loss was 50% or less (r = 0.93, n = 8, p = 0.001 and r = 0.91, n = 8, p = 0.002 respectively). Reduction of VMAT2 and DAT striatal specific binding sites strongly correlated with each other (r = 0.93, n = 14, p<0.0005). These similar changes in DAT and VMAT2 binding sites in the striatal terminal fields of the surviving nigrostriatal neurons demonstrate that there is no differential regulation of these two sites at 2 months after MPTP infusion.

Objective Development of an effective therapy to slow the inexorable progression of Parkinson disease requires a reliable, objective measurement of disease severity. In the present study, we compare pre-synaptic PET tracer uptake in the substantia nigra (SN) to cell loss and motor impairment in MPTP non-human primates. Methods Pre-synaptic PET tracers, 6-[18F]-fluorodopa (FD), [11C]-2β-methoxy-3β-4-fluorophenyltropane (CFT), and [11C]-dihydrotetrabenazine (DTBZ) were used to measure specific uptake in the SN and striatum before and after a variable dose of MPTP in non-human primates. These in vivo PET-based measures were compared with motor impairment, as well as post-mortem tyrosine hydroxylase-positive cell counts and striatal dopamine concentration. Results We found the specific uptake of CFT and DTBZ in the SN each had a strong, significant correlation with dopaminergic cell counts in the SN (R2 = 0.77, 0.53 respectively, p < .001) but FD did not. Additionally, CFT and DTBZ specific uptake in the SN each had a linear relationship with motor impairment (rs = −0.77, −0.71 respectively, p < .001) but FD did not. Interpretation Our findings demonstrate that PET measured binding potentials for CFT and DTBZ for a midbrain volume of interest targeted at the SN provide faithful correlates of nigral neuronal counts across a full range of lesion severity. Since these measures correlate with both nigral cell counts and parkinsonian ratings, we suggest that these SN PET measures are relevant biomarkers of nigrostriatal function.

Objective We evaluated the efficacy of the potent antioxidant C3 to salvage nigrostriatal neuronal function after MPTP exposure in nonhuman primates. C3 is a first-in-class functionalized water-soluble fullerene which reduces oxygen radical species associated with neurodegeneration in in vitro studies. However, C3 has not been evaluated as a neuroprotective agent in a Parkinson model in vivo. Methods Macaque fascicularis monkeys were used in a double-blind, placebo-controlled study design. MPTP-lesioned primates were given systemic C3 (n = 8) or placebo (n = 7) for two months starting one week after MPTP. Outcomes included in vivo behavioral measures of motor parkinsonism using a validated non-human primate rating scale, kinematic analyses of peak upper extremity velocity, PET imaging of 6-[18F]fluorodopa (FD, reflects dopa decarboxylase) and [11C]dihydrotetrabenazine (DTBZ; reflects vesicular monoamine transporter type 2), as well as ex vivo quantification of striatal dopamine (DA) and stereologic counts of tyrosine hydroxylase (TH) immunostained neurons in substantia nigra. Results After two months, C3 treated monkeys had significantly improved parkinsonian motor ratings, greater striatal FD and DTBZ uptake, and higher striatal dopamine levels. None of the C3 treated animals developed any toxicity. Interpretation Systemic treatment with C3 reduced striatal injury and improved motor function despite administration after the MPTP injury process had begun. These data strongly support further development of C3 as a promising therapeutic agent for PD.