Accelerated functional brain aging in pre-clinical familial Alzheimer's disease.

Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer's disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aß) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18-94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aß pathology.

Hippocampal morphology mediates biased memories of chronic pain.

Experiences and memories are often mismatched. While multiple studies have investigated psychological underpinnings of recall error with respect to emotional events, the neurobiological mechanisms underlying the divergence between experiences and memories remain relatively unexplored in the domain of chronic pain. Here we examined the discrepancy between experienced chronic low back pain (CBP) intensity (twice daily ratings) and remembered pain intensity (n = 48 subjects) relative to psychometric properties, hippocampus morphology, memory capabilities, and personality traits related to reward. 77% of CBP patients exaggerated remembered pain, which depended on their strongest experienced pain and their most recent mood rating. This bias persisted over nearly 1 year and was related to reward memory bias and loss aversion. Shape displacement of a specific region in the left posterior hippocampus mediated personality effects on pain memory bias, predicted pain memory bias in a validation CBP group (n = 21), and accounted for 55% of the variance of pain memory bias. In two independent groups (n = 20/group), morphology of this region was stable over time and unperturbed by the development of chronic pain. These results imply that a localized hippocampal circuit, and personality traits associated with reward processing, largely determine exaggeration of daily pain experiences in chronic pain patients.

Brain activity for tactile allodynia: a longitudinal awake rat functional magnetic resonance imaging study tracking emergence of neuropathic pain.

Tactile allodynia, a condition in which innocuous mechanical stimuli are perceived as painful, is a common feature of chronic pain. However, how the brain reorganizes in relation to the emergence of tactile allodynia is still largely unknown. This may stem from the fact that experiments in humans are cross-sectional in nature, whereas animal brain imaging studies typically require anaesthesia rendering the brain incapable of consciously sensing or responding to pain. In this longitudinal functional magnetic resonance imaging study in awake rats, we tracked brain activity with the development of tactile allodynia. Before injury, innocuous air-puff stimuli evoked a distributed sensory network of activations, including contralateral somatosensory cortices, thalamus, insula, and cingulate cortex. Moreover, the primary somatosensory cortex displayed a graded response tracking air-puff stimulus intensities. After neuropathic injury, and for stimuli in which the intensity exceeded the paw withdrawal threshold (evoking tactile allodynia), the blood oxygenation level-dependent response in the primary somatosensory cortex was equivalent to that evoked by the identical stimulus before injury. In contrast, nucleus accumbens and prefrontal brain areas displayed abnormal activity to normally innocuous stimuli when such stimuli induced tactile allodynia at 28 days after peripheral nerve injury, which had not been the case at 5 days after injury. Our data indicate that tactile allodynia-related nociceptive inputs are not observable in the primary somatosensory cortex BOLD response. Instead, our data suggest that, in time, tactile allodynia differentially engages neural circuits that regulate the affective and motivational components of pain.

Global disruption of degree rank order: a hallmark of chronic pain.

Chronic pain remains poorly understood; yet it is associated with the reorganization of the nervous system. Here, we demonstrate that a unitary global measure of functional connectivity, defined as the extent of degree rank order disruption, kD, identifies the chronic pain state. In contrast, local degree disruption differentiates between chronic pain conditions. We used resting-state functional MRI data to analyze the brain connectome at varying scales and densities. In three chronic pain conditions, we observe disrupted kD, in proportion to individuals' pain intensity, and associated with community membership disruption. Additionally, we observe regional degree changes, some of which were unique to each type of chronic pain. Subjects with recent onset of back pain exhibited emergence of kD only when the pain became chronic. Similarly, in neuropathic rats kD emerged weeks after injury, in proportion to pain-like behavior. Thus, we found comprehensive cross-species evidence for chronic pain being a state of global randomization of functional connectivity.

Novel method for functional brain imaging in awake minimally restrained rats.

Functional magnetic resonance imaging (fMRI) in rodents holds great promise for advancing our knowledge about human brain function. However, the use of anesthetics to immobilize rodents during fMRI experiments has restricted the type of questions that can be addressed using this technique. Here we describe an innovative procedure to train rats to be constrained without the need of any anesthesia during the whole procedure. We show that with 8-10 days of acclimation rats can be conscious and remain still during fMRI experiments under minimal stress. In addition, we provide fMRI results of conscious rodents in a variety of commonly used fMRI experimental paradigms, and we demonstrate the improved quality of these scans by comparing results when the same rodents were scanned under anesthesia. We confirm that the awake scanning procedure permits an improved evaluation of brain networks and brain response to external stimuli with minimal movement artifact. The present study further advances the field of fMRI in awake rodents, which provide more direct, forward and reverse, translational opportunities regarding brain functional correspondences between human and rodent research.

Smoking increases risk of pain chronification through shared corticostriatal circuitry.

Smoking is associated with increased incidence of chronic pain. However, the evidence is cross-sectional in nature, and underlying mechanisms remain unclear. In a longitudinal observational study, we examined the relationship between smoking, transition to chronic pain, and brain physiology. In 160 subjects with subacute back pain (SBP: back pain lasting 4-12 weeks, and no prior back pain [BP] for at least 1 year) pain characteristics, smoking status, and brain functional properties were measured repeatedly over 1 year. Sixty-eight completed the study, subdivided into recovering (SBPr, n = 31) and persisting (SBPp, n = 37), based on >20% decrease in BP over the year. Thirty-two chronic back pain (CBP: duration > 5 years) and 35 healthy controls were similarly monitored. Smoking prevalence was higher in SBP and CBP but not related to intensity of BP. In SBP, smoking status at baseline was predictive of persistence of BP 1 year from symptom onset (differentiating SBPp and SBPr with 0.62 accuracy). Smoking status combined with affective properties of pain and medication use improved prediction accuracy (0.82). Mediation analysis indicated the prediction of BP persistence by smoking was largely due to synchrony of fMRI activity between two brain areas (nucleus accumbens and medial prefrontal cortex, NAc-mPFC). In SBP or CBP who ceased smoking strength of NAc-mPFC decreased from precessation to postcessation of smoking. We conclude that smoking increases risk of transitioning to CBP, an effect mediated by corticostriatal circuitry involved in addictive behavior and motivated learning.

Functional reorganization of the default mode network across chronic pain conditions.

Chronic pain is associated with neuronal plasticity. Here we use resting-state functional magnetic resonance imaging to investigate functional changes in patients suffering from chronic back pain (CBP), complex regional pain syndrome (CRPS) and knee osteoarthritis (OA). We isolated five meaningful resting-state networks across the groups, of which only the default mode network (DMN) exhibited deviations from healthy controls. All patient groups showed decreased connectivity of medial prefrontal cortex (MPFC) to the posterior constituents of the DMN, and increased connectivity to the insular cortex in proportion to the intensity of pain. Multiple DMN regions, especially the MPFC, exhibited increased high frequency oscillations, conjoined with decreased phase locking with parietal regions involved in processing attention. Both phase and frequency changes correlated to pain duration in OA and CBP patients. Thus chronic pain seems to reorganize the dynamics of the DMN and as such reflect the maladaptive physiology of different types of chronic pain.

Role of nucleus accumbens in neuropathic pain: linked multi-scale evidence in the rat transitioning to neuropathic pain.

Despite recent evidence implicating the nucleus accumbens (NAc) as causally involved in the transition to chronic pain in humans, underlying mechanisms of this involvement remain entirely unknown. Here we elucidate mechanisms of NAc reorganizational properties (longitudinally and cross-sectionally), in an animal model of neuropathic pain (spared nerve injury [SNI]). We observed interrelated changes: (1) In resting-state functional magnetic resonance imaging (fMRI), functional connectivity of the NAc to dorsal striatum and cortex was reduced 28days (but not 5days) after SNI; (2) Contralateral to SNI injury, gene expression of NAc dopamine 1A, 2, and κ-opioid receptors decreased 28days after SNI; (3) In SNI (but not sham), covariance of gene expression was upregulated at 5days and settled to a new state at 28days; and (4) NAc functional connectivity correlated with dopamine receptor gene expression and with tactile allodynia. Moreover, interruption of NAc activity (via lidocaine infusion) reversibly alleviated neuropathic pain in SNI animals. Together, these results demonstrate macroscopic (fMRI) and molecular reorganization of NAc and indicate that NAc neuronal activity is necessary for full expression of neuropathic pain-like behavior.

Parceling human accumbens into putative core and shell dissociates encoding of values for reward and pain.

In addition to their well-established role in signaling rewarding outcomes and reward-predictive cues and in mediating positive reinforcement, there is growing evidence that nucleus accumbens (NAc) neurons also signal aversive events and cues that predict them. Here we use diffusion tractography to subdivide the right NAc into lateral-rostral (putative core, pcore) and medial-caudal (putative shell, pshell) subdivisions in humans. The two subregions exhibited differential structural connectivity, based on probabilistic tractography, to prefrontal cortical and subcortical limbic regions. We also demonstrate unique roles for each of the two subdivisions for monetary reward and thermal pain perception tasks: pshell signaling impending pain and value predictions for monetary gambles and pcore activating with anticipation of cessation of thermal pain (signaling reward value of analgesia). We examined functional connectivity for resting state, monetary reward, and thermal pain tasks, and for all three conditions observed that pcore and pshell of right NAc exhibit distinct patterns of synchrony (functional connectivity) to prefrontal cortical and subcortical limbic targets within the right hemisphere. To validate the NAc segregation, we mirrored the coordinates of right NAc pcore and pshell onto the left hemisphere and examined structural and resting state connectivity in the left hemisphere. This latter analysis closely replicated target-specific connections we obtained for the right hemisphere. Overall, we demonstrate that the human NAc can be parceled based on structural and functional connectivity, and that activity in these subdivisions differentially encodes values for expected pain relief and for expected monetary reward.

Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits.

Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain magnitude. First we compared back pain-related brain activity between subjects who have had the condition for ∼2 months with no prior history of back pain for 1 year (early, acute/subacute back pain group, n = 94), to subjects who have lived with back pain for >10 years (chronic back pain group, n = 59). In a subset of subacute back pain patients, we followed brain activity for back pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute back pain group, n = 19) and those in which the back pain persists (persistent acute/sub-acute back pain group, n = 20; based on a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to the terms pain, emotion, and reward (each map is based on >200 brain imaging studies, derived from neurosynth.org). We observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can undergo large-scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions and mechanisms of chronic pain.

Brain networks predicting placebo analgesia in a clinical trial for chronic back pain.

A fundamental question for placebo research is whether such responses are a predisposition, quantifiable by brain characteristics. We examine this issue in chronic back pain (CBP) patients who participated in a double-blind brain imaging (functional magnetic resonance imaging) clinical trial. We recently reported that when the 30 CBP participants were treated, for 2 weeks, with topical analgesic or no drug patches, pain and brain activity decreased independently of treatment type and thus were attributed to placebo responses. Here we examine in the same group brain markers for predicting placebo responses--that is, for differentiating between posttreatment persistent CBP (CBPp) and decreasing CBP (CBPd) groups. At baseline, pain and brain activity for rating spontaneous fluctuations of back pain were not different between the 2 groups. However, on the basis of brain activity differences after treatment, we identified that at baseline the extent of information shared (functional connectivity) between left medial prefrontal cortex and bilateral insula accurately (0.8) predicted posttreatment groups. This was validated in an independent cohort. Additionally, by means of frequency domain contrasts, we observe that at baseline, left dorsolateral prefrontal cortex high-frequency oscillations also predicted treatment outcomes and identified an additional set of functional connections distinguishing treatment outcomes. Combining medial and lateral prefrontal functional connections, we observe a statistically higher accuracy (0.9) for predicting posttreatment groups. These findings indicate that placebo response can be identified a priori at least in CBP, and that neuronal population interactions between prefrontal cognitive and pain processing regions predetermine the probability of placebo response in the clinical setting.

The cortical rhythms of chronic back pain.

Chronic pain is maladaptive and influences brain function and behavior by altering the flow and integration of information across brain regions. Here we use a power spectral analysis to investigate impact of presence of chronic pain on brain oscillatory activity in humans. We examine changes in BOLD fluctuations, across different frequencies, in chronic back pain (CBP) patients (n = 15) as compared to healthy controls (n = 15) during resting-state fMRI. While healthy subjects exhibited a specific, frequency band-dependent, large-scale neural organization, patients showed increased high-frequency BOLD oscillations (0.12-0.20 Hz) circumscribed mainly to medial prefrontal cortex (mPFC) and parts of the default mode network. In the patients a correlation analysis related the mPFC aberrant BOLD high-frequency dynamics to altered functional connectivity to pain signaling/modulating brain regions, thus linking BOLD frequency changes to function. We also found that increased frequency fluctuations within the mPFC were temporally synchronous with spontaneous pain changes in patients during a pain-rating task. These observations provide novel insights about the nature of CBP, identifying how it disturbs the resting brain, and link high-frequency BOLD oscillations to perception.

Timing variability in circle drawing and tapping: probing the relationship between event and emergent timing.

R. Ivry, R. M. Spencer, H. N. Zelaznik, and J. Diedrichsen (2002) have proposed a distinction between timed movements in which a temporal representation is part of the task goal (event timing) and those in which timing properties are emergent. The issue addressed in the present experiment was how timing in conditions conducive to emergent timing becomes established. According to what the authors term the transformation hypothesis, timing initially requires an event-based representation when the temporal goal is defined externally (e.g., by a metronome), but over the first few movement cycles, control processes become established that allow timing to become emergent. Different groups of participants (N = 84) executed either 1 timed interval, 4 timed intervals, or 2 timed intervals separated by a pause. They produced the intervals by either circle drawing, a task associated with emergent timing, or tapping, a task associated with event timing. Analyses of movement variability suggested that similar timing processes were used in the 2 tasks only during the 1st interval. Those results are consistent with the transformation hypothesis and lead to the inference that the transition from event-based control to emergent timing can occur rapidly during continuous movements.