Gautam Pendse

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.

Trigeminal Neuropathic Pain Alters Responses in CNS Circuits to Mechanical (Brush) and Thermal (Cold and Heat) Stimuli

Functional magnetic resonance imaging was used to study patients with chronic neuropathic pain involving the maxillary region (V2) of the trigeminal nerve in patients with spontaneous pain and evoked pain to brush (allodynia). Patients underwent two functional scans (2–3 months apart) with mechanical and thermal stimuli applied to the affected region of V2 and to the mirror site in the unaffected contralateral V2 region, as well as bilaterally to the mandibular (V3) division. Patients were stimulated with brush, noxious cold, and noxious heat. Significant changes were observed in regions within and outside the primary trigeminal sensory pathway. Stimulation to the affected (neuropathic) side resulted in predominantly frontal region and basal ganglia activation compared with the control side. The differences were consistent with the allodynia to brush and cold. A region of interest-based analysis of the trigeminal sensory pathway revealed patterns of activation that differentiated between the affected and unaffected sides and that were particular to each stimulus. Activation in the spinal trigeminal nucleus was constant in location for all pain stimuli. Activation in other brainstem nuclei also showed differences in the blood oxygenation level-dependent signal for the affected versus the unaffected side. Thus, sensory processing in patients with trigeminal neuropathic pain is associated with distinct activation patterns consistent with sensitization within and outside of the primary sensory pathway.

Painful Heat Reveals Hyperexcitability of the Temporal Pole in Interictal and Ictal Migraine States

During migraine attacks, alterations in sensation accompanying headache may manifest as allodynia and enhanced sensitivity to light, sound, and odors. Our objective was to identify physiological changes in cortical regions in migraine patients using painful heat and functional magnetic resonance imaging (fMRI) and the structural basis for such changes using diffusion tensor imaging (DTI). In 11 interictal patients, painful heat threshold + 1°C was applied unilaterally to the forehead during fMRI scanning. Significantly greater activation was identified in the medial temporal lobe in patients relative to healthy subjects, specifically in the anterior temporal pole (TP). In patients, TP showed significantly increased functional connectivity in several brain regions relative to controls, suggesting that TP hyperexcitability may contribute to functional abnormalities in migraine. In 9 healthy subjects, DTI identified white matter connectivity between TP and pulvinar nucleus, which has been related to migraine. In 8 patients, fMRI activation in TP with painful heat was exacerbated during migraine, suggesting that repeated migraines may sensitize TP. This article investigates a nonclassical role of TP in migraineurs. Observed temporal lobe abnormalities may provide a basis for many of the perceptual changes in migraineurs and may serve as a potential interictal biomarker for drug efficacy.

Aversion-related circuitry in the cerebellum: responses to noxious heat and unpleasant images.

The cerebellum is reliably activated during both acute and chronic pain conditions, but it is unclear whether the response to aversive painful stimuli can be generalized to other aversive stimuli. We hypothesized that cerebellar activation during pain reflects higher-level encoding of aversive stimuli. We used functional magnetic resonance imaging (fMRI) to compare cerebellar responses in 11 healthy volunteers to noxious heat (46°C) applied to the hand and to the passive viewing of images selected from the International Affective Picture System. Aversive stimuli in the form of noxious heat and unpleasant pictures (unpleasant vs neutral) activated overlapping areas in the posterior cerebellum, specifically in hemispheric lobule VI, Crus I, and VIIb. Pleasant pictures (pleasant vs neutral) did not share the same pattern of activation as observed with the aversive stimuli. Cerebellar areas that showed functional overlap with both heat pain and unpleasant picture viewing were significantly inversely correlated with fMRI signals measured in limbic system structures, including the anterior hypothalamus, subgenual anterior cingulate cortex, and the parahippocampal gyrus. Heat-specific functional connectivity was detected in many regions including primary motor cortex, secondary somatosensory cortex, anterior insula, and the periaqueductal gray. The overlap between cerebellar lobuli reactive to noxious heat and passive viewing of unpleasant images suggest that the cerebellum may contain specific regions involved in encoding generalized aversive processing. The separate cortical networks suggest that noxious heat-evoked responses in the cerebellum can be divided into sensorimotor and emotional networks.

Colocalized Structural and Functional Changes in the Cortex of Patients with Trigeminal Neuropathic Pain

Background Recent data suggests that in chronic pain there are changes in gray matter consistent with decreased brain volume, indicating that the disease process may produce morphological changes in the brains of those affected. However, no study has evaluated cortical thickness in relation to specific functional changes in evoked pain. In this study we sought to investigate structural (gray matter thickness) and functional (blood oxygenation dependent level – BOLD) changes in cortical regions of precisely matched patients with chronic trigeminal neuropathic pain (TNP) affecting the right maxillary (V2) division of the trigeminal nerve. The model has a number of advantages including the evaluation of specific changes that can be mapped to known somatotopic anatomy. Methodology/Principal Findings Cortical regions were chosen based on sensory (Somatosensory cortex (SI and SII), motor (MI) and posterior insula), or emotional (DLPFC, Frontal, Anterior Insula, Cingulate) processing of pain. Both structural and functional (to brush-induced allodynia) scans were obtained and averaged from two different imaging sessions separated by 2–6 months in all patients. Age and gender-matched healthy controls were also scanned twice for cortical thickness measurement. Changes in cortical thickness of TNP patients were frequently colocalized and correlated with functional allodynic activations, and included both cortical thickening and thinning in sensorimotor regions, and predominantly thinning in emotional regions. Conclusions Overall, such patterns of cortical thickness suggest a dynamic functionally-driven plasticity of the brain. These structural changes, which correlated with the pain duration, age-at-onset, pain intensity and cortical activity, may be specific targets for evaluating therapeutic interventions.

Migraine attacks the Basal Ganglia

BackgroundWith time, episodes of migraine headache afflict patients with increased frequency, longer duration and more intense pain. While episodic migraine may be defined as 1-14 attacks per month, there are no clear-cut phases defined, and those patients with low frequency may progress to high frequency episodic migraine and the latter may progress into chronic daily headache (> 15 attacks per month). The pathophysiology of this progression is completely unknown. Attempting to unravel this phenomenon, we used high field (human) brain imaging to compare functional responses, functional connectivity and brain morphology in patients whose migraine episodes did not progress (LF) to a matched (gender, age, age of onset and type of medication) group of patients whose migraine episodes progressed (HF).ResultsIn comparison to LF patients, responses to pain in HF patients were significantly lower in the caudate, putamen and pallidum. Paradoxically, associated with these lower responses in HF patients, gray matter volume of the right and left caudate nuclei were significantly larger than in the LF patients. Functional connectivity analysis revealed additional differences between the two groups in regard to response to pain.ConclusionsSupported by current understanding of basal ganglia role in pain processing, the findings suggest a significant role of the basal ganglia in the pathophysiology of the episodic migraine.

Robust reproducible resting state networks in the awake rodent brain.

Resting state networks (RSNs) have been studied extensively with functional MRI in humans in health and disease to reflect brain function in the un-stimulated state as well as reveal how the brain is altered with disease. Rodent models of disease have been used comprehensively to understand the biology of the disease as well as in the development of new therapies. RSN reported studies in rodents, however, are few, and most studies are performed with anesthetized rodents that might alter networks and differ from their non-anesthetized state. Acquiring RSN data in the awake rodent avoids the issues of anesthesia effects on brain function. Using high field fMRI we determined RSNs in awake rats using an independent component analysis (ICA) approach, however, ICA analysis can produce a large number of components, some with biological relevance (networks). We further have applied a novel method to determine networks that are robust and reproducible among all the components found with ICA. This analysis indicates that 7 networks are robust and reproducible in the rat and their putative role is discussed.

Excitatory neurotransmitters in brain regions in interictal migraine patients

ObjectiveTo examine biochemical differences in the anterior cingulate cortex (ACC) and insula during the interictal phase of migraine patients. We hypothesized that there may be differences in levels of excitatory amino acid neurotransmitters and/or their derivatives in migraine group based on their increased sensitivity to pain.Methods2D J-resolved proton magnetic resonance spectroscopy (1H-MRS) data were acquired at 4.0 Tesla (T) from the ACC and insula in 10 migraine patients (7 women, 3 men, age 43 ± 11 years) and 8 age gender matched controls (7 women, 3 men, age 41 ± 9 years).ResultsStandard statistical analyses including analysis of variance (ANOVA) showed no significant metabolite differences between the two subject cohorts in the ACC nor the insula. However, linear discriminant analysis (LDA) introduced a clear separation between subject cohorts based on N-acetyl aspartylglutamate (NAAG) and glutamine (Gln) in the ACC and insula.ConclusionThese results are consistent with glutamatergic abnormalities in the ACC and insula in migraine patients during their interictal period compared to healthy controls. An alteration in excitatory amino acid neurotransmitters and their derivatives may be a contributing factor for migraineurs for a decrease in sensitivity for migraine or a consequence of the chronic migraine state. Such findings, if extrapolated to other regions of the brain would offer new opportunities to modulate central system as interictal or preemptive medications in these patients.

BOLD Responses in Somatosensory Cortices Better Reflect Heat Sensation than Pain

The discovery of cortical networks that participate in pain processing has led to the common generalization that blood oxygen level-dependent (BOLD) responses in these areas indicate the processing of pain. Physical stimuli have fundamental properties that elicit sensations distinguishable from pain, such as heat. We hypothesized that pain intensity coding may reflect the intensity coding of heat sensation during the presentation of thermal stimuli during fMRI. Six 3T fMRI heat scans were collected for 16 healthy subjects, corresponding to perceptual levels of “low innocuous heat,” “moderate innocuous heat,” “high innocuous heat,” “low painful heat,” “moderate painful heat,” and “high painful heat” delivered by a contact thermode to the face. Subjects rated pain and heat intensity separately after each scan. A general linear model analysis detected different patterns of brain activation for the different phases of the biphasic response to heat. During high painful heat, the early phase was associated with significant anterior insula and anterior cingulate cortex activation. Persistent responses were detected in the right dorsolateral prefrontal cortex and inferior parietal lobule. Only the late phase showed significant correlations with perceptual ratings. Significant heat intensity correlated activation was identified in contralateral primary and secondary somatosensory cortices, motor cortex, and superior temporal lobe. These areas were significantly more related to heat ratings than pain. These results indicate that heat intensity is encoded by the somatosensory cortices, and that pain evaluation may either arise from multimodal evaluative processes, or is a distributed process.

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.