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Biomedical subjects

David Borsook

Publications and source records attributed to David Borsook.

18 recordsLinked to original sources
PubMed2006

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.

Adult↗
PubMed2006

Breaking down the barriers: fMRI applications in pain, analgesia and analgesics.

This review summarizes functional magnetic resonance imaging (fMRI) findings that have informed our current understanding of pain, analgesia and related phenomena, and discusses the potential role of fMRI in improved therapeutic approaches to pain. It is divided into 3 main sections: (1) fMRI studies of acute and chronic pain. Physiological studies of pain have found numerous regions of the brain to be involved in the interpretation of the 'pain experience'; studies in chronic pain conditions have identified a significant CNS component; and fMRI studies of surrogate models of chronic pain are also being used to further this understanding. (2) fMRI studies of endogenous pain processing including placebo, empathy, attention or cognitive modulation of pain. (3) The use of fMRI to evaluate the effects of analgesics on brain function in acute and chronic pain. fMRI has already provided novel insights into the neurobiology of pain. These insights should significantly advance therapeutic approaches to chronic pain.

Analgesia↗
PubMed2006

Food intake and reward mechanisms in patients with schizophrenia: implications for metabolic disturbances and treatment with second-generation antipsychotic agents.

Obesity is highly prevalent among patients with schizophrenia and is associated with detrimental health consequences. Although excessive consumption of fast food and pharmacotherapy with such second-generation antipsychotic agents (SGAs) as clozapine and olanzapine has been implicated in the schizophrenia/obesity comorbidity, the pathophysiology of this link remains unclear. Here, we propose a mechanism based on brain reward function, a relevant etiologic factor in both schizophrenia and overeating. A comprehensive literature search on neurobiology of schizophrenia and of eating behavior was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) energy homeostasis, (2) food reward and hedonics, (3) reward function in schizophrenia, and (4) metabolic effects of the SGAs. A mesolimbic hyperdopaminergic state may render motivational/incentive reward system insensitive to low salience/palatability food. This, together with poor cognitive control from hypofunctional prefrontal cortex and enhanced hedonic impact of food, owing to exaggerated opioidergic drive (clinically manifested as pain insensitivity), may underlie unhealthy eating habits in patients with schizophrenia. Treatment with SGAs purportedly improves dopamine-mediated reward aspects, but at the cost of increased appetite and worsened or at least not improved opiodergic capacity. These effects can further deteriorate eating patterns. Pathophysiological and therapeutic implications of these insights need further validation via prospective clinical trials and neuroimaging studies.

Animals↗
PubMed2006

Reward-aversion circuitry in analgesia and pain: implications for psychiatric disorders.

Sensory and emotional systems normally interact in a manner that optimizes an organism's ability to survive using conscious and unconscious processing. Pain and analgesia are interpreted by the nervous system as aversive and rewarding processes that trigger specific behavioral responses. Under normal physiological conditions these processes are adaptive. However, under chronic pain conditions, functional alterations of the central nervous system frequently result in maladaptive behaviors. In this review, we examine: (a) the interactions between sensory and emotional systems involved in processing pain and analgesia in the physiological state; (b) the role of reward/aversion circuitry in pain and analgesia; and (c) the role of alterations in reward/aversion circuitry in the development of chronic pain and co-morbid psychiatric disorders. These underlying features have implications for understanding the neurobiology of functional illnesses such as depression and anxiety and for the development and evaluation of novel therapeutic interventions.

Adaptation, Physiological↗
PubMed2006

A role for fMRI in optimizing CNS drug development.

Drug development today needs to balance agility, speed and risk in defining the probability of success for molecules, mechanisms and therapeutic concepts. New techniques in functional magnetic resonance imaging (fMRI) promise to be part of a sequence that could transform drug development for disorders of the central nervous system (CNS) by examining brain systems and their functional activation dynamically. The brain is complex and multiple transmitters and intersecting brain circuits are implicated in many CNS disorders. CNS therapeutics are designed against specific CNS targets, many of which are unprecedented. The challenge is to reveal the functional consequences of these interactions to assess therapeutic potential. fMRI can help optimize CNS drug discovery by providing a key metric that can increase confidence in early decision-making, thereby improving success rates and reducing risk, development times and costs of drug development.

Animals↗
PubMed2006

Functional imaging of the trigeminal system: applications to migraine pathophysiology.

BACKGROUND: Based largely on data from animal models, migraine is hypothesized to involve changes in neural function in brain areas that mediate nociception--specifically, the trigeminal nerve, spinal trigeminal nucleus, and thalamus. These hypotheses about migraine pathophysiology can be tested directly in humans for the first time, with recent advances in functional neuroimaging techniques, which allow assessment of functional activity of specific brain areas. This article discusses the hypothesized role of the trigeminovascular pain system in migraine, reviews recent findings involving functional imaging of the human trigeminal system, and considers applications of functional imaging in the study of migraine pathophysiology. Functional neuroimaging is the only noninvasive approach for the objective measurement of changes in neural activity in humans. Functional magnetic resonance imaging has been applied to the measurement of neural activation of the trigeminal nociceptive system in healthy volunteers, and in patients with pain syndromes such as trigeminal pain. CONCLUSIONS: The demonstrated utility of functional magnetic resonance imaging at elucidating, in a regionally specific manner, the functional and temporal changes in neural activity in the trigeminal nociceptive system, promises to make it a useful tool for the study of migraine pathophysiology and the evaluation of therapeutic interventions.

Humans↗
PubMed2006

Functional magnetic resonance imaging measures of the effects of morphine on central nervous system circuitry in opioid-naive healthy volunteers.

In this pilot study, we used functional magnetic resonance imaging (fMRI) to study the effects of morphine in 8 healthy, opioid-naïve volunteers. Intravenous small-dose morphine (4 mg/70 kg) or saline was administered to volunteers undergoing a fMRI scan. Infusion of morphine, but not saline, elicited mild euphoria without aversive symptoms and resulted in positive signal changes in reward structures including the nucleus accumbens, sublenticular extended amygdala, orbitofrontal cortex, and hippocampus. The positive signal in the accumbens was opposite to the signal previously reported for noxious stimuli. Morphine produces a decreased signal in cortical areas in a similar manner to sedative-hypnotic drugs such as propofol or midazolam. Activation in endogenous analgesic regions was observed in the periaqueductal gray, the anterior cingulate gyrus (decreased signal), and hypothalamus (increased signals). The pattern of activation in reward circuitry was similar to that reported for euphoric drugs of abuse, providing a model to evaluate the initial effects of morphine on the central nervous system components of the circuitry involved in addiction. The segregation of fMRI response that was observed in cortical versus subcortical regions suggests a dissociation of reward from sensory-motor and cognitive functions. Activation patterns were opposite to those previously observed for the mu antagonist, naloxone.

Adult↗
PubMed2005

Behavioral and pharmacological characterization of a distal peripheral nerve injury in the rat.

Previous rat neuropathic pain models have utilized peripheral nerve injuries that damage a significant proportion of large nerves such as the sciatic nerve or its divisions. Injuries that lead to neuropathic pain in humans may involve the peripheral extremities. The current study evaluated the behavioral effects of injury to the plantar nerves in the rat (distal nerve injury-DNI). A delayed onset of hypersensitivity to an innocuous mechanical stimulus was observed following cutting of the left plantar nerves, whereas mechanical hypersensitivity developed more rapidly in rats with either an injury near the sciatic nerve trunk (chronic constriction injury (CCI), spared nerve injury (SNI)) or a spinal nerve root (spinal nerve ligation (SNL). Similar to other nerve injury pain models, rats with injured plantar nerves also developed an early onset and persistent sensitivity to a cooling stimulus. The effects of morphine, gabapentin and imipramine on mechanical and cold hypersensitivity were evaluated in rats with a DNI, CCI and SNI. In all three models, morphine dose-dependently suppressed mechanical and cold hypersensitivity, whereas gabapentin only suppressed mechanical hypersensitivity. Imipramine had no effect on either cold or mechanical hypersensitivity in any of the nerve-injured rats. The pharmacological data suggest that the underlying basis of neuropathic pain may be similar irrespective of the site of nerve injury.

Amines↗
PubMed2005

The effect of antinociceptive drugs tested at different times after nerve injury in rats.

Given the evolving nature of anatomical and functional changes in the nervous system that are involved in the development of neuropathic pain, it is possible that the differing time course after injury underlies the inconsistent efficacy of drugs in neuropathic pain patients. In the current study, we evaluated the behavioral effects of two standard drugs used clinically for neuropathic pain, the anticonvulsant gabapentin and antidepressant imipramine, in rats at different times after peripheral nerve injury. Rats that underwent the spared nerve injury procedure responded to an innocuous mechanical stimulus (von Frey filament) 2, 4, and 8 wk after injury. Gabapentin dose-dependently suppressed mechanical sensitivity at all time points tested but the potency of gabapentin was three-fold less 4 wk postinjury (135 mg/kg) compared with 2 and 8 wk postinjury (41 and 44 mg/kg, respectively). In contrast, imipramine lacked significant efficacy at 2 and 8 wk postinjury but slightly attenuated mechanical hypersensitivity at 4 wk postinjury. The results show that drug effects may change over time in the neuropathic state, which should be an important consideration in the evaluation of drugs in preclinical animal pain models and has implications for temporal approaches to therapy in the clinic.

Amines↗
PubMed2004

Functional imaging of the human trigeminal system: opportunities for new insights into pain processing in health and disease.

Peripheral inflammation or nerve damage result in changes in nervous system function, and may be a source of chronic pain. A number of animal studies have indicated that central neural plasticity, including sensitization of neurons within the spinal cord and brain, is part of the response to nervous system insult, and can result in the appearance of altered sensation, including pain. It cannot be assumed, however, that data obtained from animal models unambiguously reflects CNS changes that occur in humans. Currently, the only noninvasive approach to determining objective changes in neural processing and responsiveness within the CNS in humans is the use of functional imaging techniques. It is now possible to use functional magnetic resonance imaging (fMRI) to measure CNS activation in the trigeminal ganglion, spinal trigeminal nucleus, the thalamus, and the somatosensory cortex in healthy volunteers, in a surrogate model of hyperalgesia, and in patients with trigeminal pain. By offering a window into the temporal and functional changes that occur in the damaged nervous system in humans, fMRI can provide both insight into the mechanisms of normal and pathological pain and, potentially, an objective method for measuring altered sensation. These advances are likely to contribute greatly to the diagnosis and treatment of clinical pain conditions affecting the trigeminal system (e.g., neuropathic pain, migraine).

Humans↗
PubMed2004

Antineuropathic effects of the antibiotic derivative spicamycin KRN5500.

Excellence in neuropathic pain management continues to challenge the ability of health care providers. Current medications are helpful but often create significant side effects or simply fail to provide adequate analgesia. We report here on a serendipitous finding of the successful attenuation of neuropathic pain in a patient with long-standing monoclonal gammopathy, Raynaud's disease, and neuropathic pain who received the trial chemotherapeutic agent KRN5500. This finding led to animal studies that have provided support for the possible use of KRN5500 in the treatment of neuropathic pain in humans as well as some insight into the possible mechanism(s) of action of this drug.

Aged↗
PubMed2003

Pain imaging: future applications to integrative clinical and basic neurobiology.

We have entered a new era in understanding CNS circuitry involved in acute and chronic pain. The ability to objectively measure a pain or analgesic state of the brain using non-invasive methods that define neural activation provides the possibility for top-down approaches to drug discovery. These brain maps represent the specific brain state. In the future, correlations with such states and behavioral, genetic, epigenetic or other chemical markers may help define specific diagnostic tools and novel approaches to drug discovery.

Animals↗
PubMed2003

Specific and somatotopic functional magnetic resonance imaging activation in the trigeminal ganglion by brush and noxious heat.

We used functional magnetic resonance imaging (fMRI) to assess activation in the trigeminal ganglion during innocuous mechanical (brush) and noxious thermal (46 degrees C) stimulation of the face within the receptive fields of each of the three divisions of the trigeminal nerve in healthy volunteers. For both stimulus types, we observed signal changes only in the ipsilateral ganglion, and activation occurred somatotopically, as predicted by the known anatomical segregation of the neurons comprising the ophthalmic (V1), maxillary (V2), and mandibular (V3) divisions of the nerve. Signal decreased after brush stimuli and increased after the application of noxious heat. The abilities to detect somatotopic activation within the ganglion and to segregate non-noxious mechanical from noxious thermal stimuli suggest that fMRI will be valuable for measuring changes in the trigeminal ganglion in human models of neuropathic pain and in the clinical condition itself and may also be useful in the evaluation of pain therapies.

Adult↗
PubMed2003

Neural circuitry underlying pain modulation: expectation, hypnosis, placebo.

The ability to predict the likelihood of an aversive event is an important adaptive capacity. Certainty and uncertainty regarding pain cause different adaptive behavior, emotional states, attentional focus, and perceptual changes. Recent functional neuroimaging studies indicate that certain and uncertain expectation are mediated by different neural pathways-the former having been associated with activity in the rostral anterior cingulate cortex and posterior cerebellum, the latter with activation changes in the ventromedial prefrontal cortex, mid-cingulate cortex and hippocampus. Expectation plays an important role not only in its modulation of acute and chronic pain, but also in other disorders which are characterized by certain expectation (specific phobias) or uncertain expectation (generalized anxiety disorder) of aversive events.

Journal Article↗
PubMed2002

Somatotopic activation in the human trigeminal pain pathway.

Functional magnetic resonance imaging was used to image pain-associated activity in three levels of the neuraxis: the medullary dorsal horn, thalamus, and primary somatosensory cortex. In nine subjects, noxious thermal stimuli (46 degrees C) were applied to the facial skin at sites within the three divisions of the trigeminal nerve (V1, V2, and V3) and also to the ipsilateral thumb. Anatomical and functional data were acquired to capture activation across the spinothalamocortical pathway in each individual. Significant activation was observed in the ipsilateral spinal trigeminal nucleus within the medulla and lower pons in response to at least one of the three facial stimuli in all applicable data sets. Activation from the three facial stimulation sites exhibited a somatotopic organization along the longitudinal (rostrocaudal) axis of the brain stem that was consistent with the classically described "onion skin" pattern of sensory deficits observed in patients after trigeminal tractotomy. In the thalamus, activation was observed in the contralateral side involving the ventroposteromedial and dorsomedial nuclei after stimulation of the face and in the ventroposterolateral and dorsomedial nuclei after stimulation of the thumb. Activation in the primary somatosensory cortex displayed a laminar sequence that resembled the trigeminal nucleus, with V2 more rostral, V1 caudal, and V3 medial, abutting the region of cortical activation observed for the thumb. These results represent the first simultaneous imaging of pain-associated activation at three levels of the neuraxis in individual subjects. This approach will be useful for exploring central correlates of plasticity in models of experimental and clinical pain.

Adult↗
PubMed2002

Utilizing brain imaging for analgesic drug development.

Analgesia is defined as loss of pain sensation without loss of consciousness; pain may be acute or chronic. Acute pain is well understood and can be controlled with currently available analgesics. Chronic pain, however, is not effectively controlled with current analgesics and side effect profiles often limit the use of these agents. Currently there are: (i) no objective methods for defining pain or analgesia in humans; (ii) no objective methods for correlating efficacy of analgesics in animal testing with human testing; and (iii) no objective method of evaluating the efficacy of analgesics in painful conditions, including neuropathic pain in which adaptive or maladaptive changes evolve with time. A technological revolution in functional brain imaging in humans and animals offers new approaches to objective evaluation of analgesics and of clinical pain states. These approaches hold great promise for revolutionizing drug development at preclinical and clinical stages.

Analgesics↗