Jaymin Upadhyay

Alterations in brain structure and functional connectivity in prescription opioid-dependent patients.

A dramatic increase in the use and dependence of prescription opioids has occurred within the last 10 years. The consequences of long-term prescription opioid use and dependence on the brain are largely unknown, and any speculation is inferred from heroin and methadone studies. Thus, no data have directly demonstrated the effects of prescription opioid use on brain structure and function in humans. To pursue this issue, we used structural magnetic resonance imaging, diffusion tensor imaging and resting-state functional magnetic resonance imaging in a highly enriched group of prescription opioid-dependent patients [(n=10); from a larger study on prescription opioid dependent patients (n=133)] and matched healthy individuals (n=10) to characterize possible brain alterations that may be caused by long-term prescription opioid use. Criteria for patient selection included: (i) no dependence on alcohol or other drugs; (ii) no comorbid psychiatric or neurological disease; and (iii) no medical conditions, including pain. In comparison to control subjects, individuals with opioid dependence displayed bilateral volumetric loss in the amygdala. Prescription opioid-dependent subjects had significantly decreased anisotropy in axonal pathways specific to the amygdala (i.e. stria terminalis, ventral amygdalofugal pathway and uncinate fasciculus) as well as the internal and external capsules. In the patient group, significant decreases in functional connectivity were observed for seed regions that included the anterior insula, nucleus accumbens and amygdala subdivisions. Correlation analyses revealed that longer duration of prescription opioid exposure was associated with greater changes in functional connectivity. Finally, changes in amygdala functional connectivity were observed to have a significant dependence on amygdala volume and white matter anisotropy of efferent and afferent pathways of the amygdala. These findings suggest that prescription opioid dependence is associated with structural and functional changes in brain regions implicated in the regulation of affect and impulse control, as well as in reward and motivational functions. These results may have important clinical implications for uncovering the effects of long-term prescription opioid use on brain structure and function.

A key role of the basal ganglia in pain and analgesia - insights gained through human functional imaging

The basal ganglia (BG) are composed of several nuclei involved in neural processing related to the execution of motor, cognitive and emotional activities. Preclinical and clinical data have implicated a role for these structures in pain processing. Recently neuroimaging has added important information on BG activation in conditions of acute pain, chronic pain and as a result of drug effects. Our current understanding of alterations in cortical and sub-cortical regions in pain suggests that the BG are uniquely involved in thalamo-cortico-BG loops to integrate many aspects of pain. These include the integration of motor, emotional, autonomic and cognitive responses to pain.

Default-Mode-Like Network Activation in Awake Rodents

During wakefulness and in absence of performing tasks or sensory processing, the default-mode network (DMN), an intrinsic central nervous system (CNS) network, is in an active state. Non-human primate and human CNS imaging studies have identified the DMN in these two species. Clinical imaging studies have shown that the pattern of activity within the DMN is often modulated in various disease states (e.g., Alzheimers, schizophrenia or chronic pain). However, whether the DMN exists in awake rodents has not been characterized. The current data provides evidence that awake rodents also possess ‘DMN-like’ functional connectivity, but only subsequent to habituation to what is initially a novel magnetic resonance imaging (MRI) environment as well as physical restraint. Specifically, the habituation process spanned across four separate scanning sessions (Day 2, 4, 6 and 8). At Day 8, significant (p<0.05) functional connectivity was observed amongst structures such as the anterior cingulate (seed region), retrosplenial, parietal, and hippocampal cortices. Prior to habituation (Day 2), functional connectivity was only detected (p<0.05) amongst CNS structures known to mediate anxiety (i.e., anterior cingulate (seed region), posterior hypothalamic area, amygdala and parabracial nucleus). In relating functional connectivity between cingulate-default-mode and cingulate-anxiety structures across Days 2-8, a significant inverse relationship (r = −0.65, p = 0.0004) was observed between these two functional interactions such that increased cingulate-DMN connectivity corresponded to decreased cingulate anxiety network connectivity. This investigation demonstrates that the cingulate is an important component of both the rodent DMN-like and anxiety networks.

Effective and Structural Connectivity in the Human Auditory Cortex

Language processing involves multiple neuronal structures in the human auditory cortex. Although a variety of neuroimaging and mapping techniques have been implemented to better understand language processing at the level of the auditory cortex, much is unknown regarding how and by what pathways these structures interact during essential tasks such as sentence comprehension. In this study, the effective and structural connectivity at the level of the auditory cortex were investigated. First, blood oxygenation level-dependent (BOLD) responses were measured with time-resolved functional magnetic resonance imaging (fMRI) during audition of short sentences. Once BOLD activation maps were obtained, the effective connectivity between primary auditory cortex and the surrounding auditory regions on the supratemporal plane and superior temporal gyrus (STG) were investigated using Granger causality mapping (GCM). Effective connectivity was observed between the primary auditory cortex and (1) the lateral planum polare and anterior STG, and (2) the lateral planum temporale and posterior STG. By using diffusion tensor probabilistic mapping (DTPM), rostral and caudal fiber pathways were detected between regions depicting effective connectivity. The effective and structural connectivity results of the present study provide further insight as to how auditory stimuli (i.e., human language) is processed at the level of the auditory cortex. Furthermore, combining BOLD fMRI-based GCM and DTPM analysis could provide a novel means to study effective and structural connectivity not only in the auditory cortex, but also in other cortical regions.

Diffusion tensor spectroscopy and imaging of the arcuate fasciculus

The arcuate fasciculus (AF) is a fiber pathway in the human brain relevant for language processes and has recently been characterized by means of diffusion tensor tractography. The observations made concerning the left and right hemisphere AF include a characterization of the trajectories and quantification of physical properties such as fractional anisotropy, DTI-based fiber density and volume. However, these observations were based on the diffusion of water, which is not particular to either the intra- or extra-axonal compartments, and thus its usefulness for tissue characterization is limited. If the diffusion properties and in turn the geometric properties of only one tissue compartment can be isolated and characterized, a better microstructural characterization of AF is possible. In this study, water-based diffusion tensor probabilistic mapping was first implemented to segment the AF. Subsequently, diffusion tensor spectroscopic measurements of N-acetyl aspartate (NAA) were performed to measure the intra-axonal specific diffusion in left and right AF. Diffusion properties of NAA, which solely reflect the intra-axonal space, indicated possible leftward asymmetry in axonal diameter, where those of water, which are not compartment-specific, showed laterality to a lesser extent.

Imaging Drugs with and without Clinical Analgesic Efficacy

The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with μ-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK1 receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts.

Direct optic nerve pulvinar connections defined by diffusion MR tractography in humans: Implications for photophobia

The pathway that underlies exacerbation of migraine headache by light has not been elucidated in the human brain but has recently been reported in a rodent model. We employ diffusion weighted imaging and probabilistic tractography to map connectivity of direct pathways from the optic nerve to the pulvinar implicated with whole‐body allodynia during migraine. Nine healthy subjects were recruited to the study and underwent scanning on a 3T magnet. We were able to define well‐known image‐forming (optic nerve ‐> lateral geniculate ‐> visual cortex) as well as a less known nonimage forming visual pathway from the optic chiasm to the pulvinar, and from the pulvinar to several associative cortical brain regions. Such pathway may allow photic signals to converge on a thalamic region we described recently to be selectively activated during migraine headache. Consistent with physiological and anatomical studies in rats, the data provide an anatomical substrate for exacerbation of migraine headache by light in the human. Hum Brain Mapp, 2012.

Noninvasive mapping of human trigeminal brainstem pathways

The human trigeminal system mediates facial pain and somatosensory processing. The anatomic location of neuronal substrates and axonal pathways of the trigeminal system have previously been characterized with conventional in vitro methods. The present investigation implemented diffusion tensor imaging (DTI) and probabilistic tractography to first segment the peripheral trigeminal circuitry, trigeminal nerve branches (ophthalmic, maxillary, and mandibular nerves), ganglion, and nerve root. Subsequent segmentations involved the spinal trigeminal and trigeminal thalamic tracts, which respectively convey information to the spinal trigeminal nuclei and ventral thalamic regions. This latter procedure also identified 1) spinal thalamic (anterolateral [AL]) system pathways (propagating pain and temperature information from the body), 2) trigeminal lemniscus (TL; touch and face position), and 3) medial lemniscus (ML; touch and limb position). The anatomic location of the identified pain and somatosensory pathways compared well with previous functional findings in the human trigeminal system, as well as the tract position in human histological cross sections. Probabilistic tractography may be a useful method to further comprehend the functional and structural properties of trigeminal and other related systems. Application of DTI to map pain and somatosensory pathways in conjunction with a characterization of function properties of pain and somatosensory processing would further define the systematic changes that occur in trigeminal pathology. Magn Reson Med 60:1037–1046, 2008.

Diffusion properties of NAA in human corpus callosum as studied with diffusion tensor spectroscopy.

In diffusion tensor imaging (DTI) the anisotropic movement of water is exploited to characterize microstructure. One confounding issue of DTI is the presence of intra‐ and extracellular components contributing to the measured diffusivity. This causes an ambiguity in determining the underlying cause of diffusion properties, particularly the fractional anisotropy (FA). In this study an intracellular constituent, N‐acetyl aspartate (NAA), was used to probe intracellular diffusion, while water molecules were used to probe the combined intra‐ and extracellular diffusion. NAA and water diffusion measurements were made in anterior and medial corpus callosum (CC) regions, which are referred to as R1 and R2, respectively. FA(NAA) was found to be greater than FA(Water) in both CC regions, thus indicating a higher degree of anisotropy within the intracellular space in comparison to the combined intra‐ and extracellular spaces. A decreasing trend in the FA of NAA and water was observed between R1 and R2, while the radial diffusivity (RD) for both molecules increased. The increase in RD(NAA) is particularly significant, thus explaining the more significant decrease in FA(NAA) between the two regions. It is suggested that diffusion tensor spectroscopy of NAA can potentially be used to further characterize microscopic anatomic organization in white matter. Magn Reson Med 58:1045–1053, 2007.

Modulation of CNS pain circuitry by intravenous and sublingual doses of buprenorphine.

Buprenorphine (BUP) is a partial agonist at μ-, δ- and ORL1 (opioid receptor-like)/nociceptin receptors and antagonist at the κ-opioid receptor site. BUP is known to have both analgesic as well as antihyperalgesic effects via its central activity, and is used in the treatment of moderate to severe chronic pain conditions. Recently, it was shown that intravenous (IV) administration of 0.2mg/70 kg BUP modulates the blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) response to acute noxious stimuli in healthy human subjects. The present study extends these observations by investigating the effects of BUP dose and route of administration on central nervous system (CNS) pain circuitry. Specifically, the modulation of evoked pain BOLD responses and resting state functional connectivity was measured following IV (0.1 and 0.2mg/70 kg) and sublingual (SL) (2mg) BUP administration in healthy human subjects. While 0.1mg/70 kg IV BUP is sub-analgesic, both 0.2mg/70 kg IV BUP and 2.0mg SL BUP are analgesic doses of the drug. Evoked BOLD responses were clearly modulated in a dose-dependent manner. The analgesic doses of BUP by both routes of administration yielded a potentiation in limbic/mesolimbic circuitry and attenuation in sensorimotor/sensory-discriminative circuitry. In addition, robust decreases in functional connectivity between the putamen and the sensorimotor/sensory-discriminative structures were observed at the two analgesic doses subsequent to measuring the maximum plasma BUP concentrations (C(max)). The decreases in functional connectivity within the sensorimotor/sensory-discriminative circuitry were also observed to be dose-dependent in the IV administration cohorts. These reproducible and consistent functional CNS measures at clinically effective doses of BUP demonstrate the potential of evoked pain fMRI and resting-state functional connectivity as objective tools that can inform the process of dose selection. Such methods may be useful during early clinical phase evaluation of potential analgesics in drug development.