- Email: [email protected]
Cutaneous α-synuclein and Parkinson Disease, a biomarker of disease severity
Abstracts / Autonomic Neuroscience: Basic and Clinical 177 (2013) 1–65
Anderson (Department of Anatomy and Neuroscience, The University of Melbourne, VIC 3010 Australia) We compared in vivo cell cycle dynamics of developing thoracic dorsal root ganglia (DRG) and sympathetic stellate ganglia (StG). We used Sox10-immunohistochemistry to mark neural crest cells (NCCs) and glial cells and Tuj1 to mark neuroblasts and neurons. In the DRG, from E9.5-E11.5, the proportion of cycling cells (the growth fraction, GF) for NCCs (Sox10+ cells) is 100%, the cell cycle length (Tc) is short (~10 h) and S-phase (Ts) accounts for ~65% of the Tc. This ratio of Ts/Tc is maintained up until E13.5 when Tc dramatically increases and Ts shortens. This corresponds to when the first Sox10+ cells withdraw from the cell cycle. The first DRG neurons, marked by expression of Tuj1, appear between E9.5 and E10.5 as they withdraw permanently from the cell cycle. In the StG at E9.5, division of Sox10+ NCCs is rapid (Tc = 10.6 h) with a relatively long Ts. At E10.5, Sox10+ cells lengthened their Tc to 38 h and the Ts decreased. The first StG neuroblasts (Tuj1+ cells) appear on E10.5 and immediately exit the cell cycle, only to re-enter the cell cycle one day later at E11.5, when N80% of cells in the StG were Tuj1+ neuroblasts. Tuj1+ neuroblasts continued to cycle, with the first neuroblasts withdrawing permanently from the cell cycle after E12.5. While the pattern of proliferation was quite different in the two ganglia, with StG neuroblasts re-entering the cell cycle and continuing to proliferate rapidly after differentiation while DRG neurons permanently withdraw from the cell cycle on differentiation, in both tissues major changes in patterns of proliferation were marked by dramatic changes in cell cycle dynamics. This is consistent with the idea that significant changes in cell cycle parameters can alter the time available for signals to effect changes in cell behaviour.
27
patients for 12 months. Patients were randomized to rifampicin 300 mg twice daily or matching placebo. The primary outcome measure was the rate of change from baseline to 12 months in UMSARS I. Other outcome measures included the rate of change in UMSARS II and in total UMSARS (I + II), and change in autonomic symptoms (COMPASS_select). In addition, patients recruited at the Mayo site (n = 19) also underwent standardized autonomic testing in addition to clinical and laboratory evaluations at baseline and study completion. Sudomotor, cardiovagal, and adrenergic deficits were quantified on a composite autonomic severity scale (CASS, range 0-10). Thermoregulatory sweat test was performed to derive anterior body anhidrosis (TST%, 0-100). Results: Patients had possible (48%) or probable (52%) MSA; 38% were women. The mean age was 61.0 ± 8.5 (mean ± SD); 11 subjects withdrew prematurely. The study was stopped after pre-planned interim analysis met futility criteria. UMSARS I slopes were 0.50 ± 0.50 and 0.50 ± 0.70 in the placebo and rifampicin arms, respectively (P = 0.817). UMSARS II and total UMSARS slopes and the change in COMPASS_select were also not significantly different. Of the patients enrolled at Mayo, 10 received rifampicin, 9 placebo. CASS was 6.5 ± 2.8 versus 6.4 ± 2.3 at baseline and 7.2 ± 2.7 versus 6.9 ± 2.0 following treatment (rifampicin versus placebo, change p = 0.96). TST% was 31.4 ± 30.5 versus 48.4 ± 32.5 at baseline and 34.7 ± 27.6 versus 53.8 ± 38.6 following treatment (change p = 0.44). Conclusions: There was no significant effect of rifampicin in MSA, neither on the progression of clinical parameters, nor on progression of autonomic symptoms and deficits. Supported by NIH (P01NS44233, U54NS065736, K23NS075141, UL1RR24150) and Mayo Funds.
doi:10.1016/j.autneu.2013.05.035
doi:10.1016/j.autneu.2013.05.036
Abstract 7.4
Abstract 7.5
Randomized Trial of Rifampicin in MSA: Primary Outcomes and Effect on Autonomic Function
Cutaneous α-synuclein and Parkinson Disease, a biomarker of disease severity
W. Singer (Mayo Clinic, Rochester, MN, United States), D. Robertson (Vanderbilt University, Nashville, TN, United States), S. Gilman (University of Michigan, Ann Arbor, MI, United States), H. Kaufmann (New York University Medical Center, New York, NY, United States), I. Biaggioni (Vanderbilt University, Nashville, TN, United States), R. Freeman (Beth Israel Medical Center, Boston, MA, United States), R.D. Fealey, J. Mandrekar (Mayo Clinic, Rochester, MN, United States), W. Dupont (Vanderbilt University, Nashville, TN, United States), T.L. Gehrking, J.D. Schmelzer, D.M. Sletten, J.A. Gehrking, P.A. Low (Mayo Clinic, Rochester, MN, United States)
Ningshan Wang, Christopher H. Gibbons, Roy Freeman (Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA)
Objective: To determine the effect of rifampicin on clinical progression and progression of autonomic failure in multiple system atrophy (MSA).
Background: Parkinson disease is a multisystem neurodegenerative disease with deposition of α-synuclein in the central, peripheral and enteric nervous systems. The most prominent manifestations of Parkinson disease are due to central, motor system neurodegeneration but there is also widespread peripheral, autonomic and enteric nervous system degeneration with associated clinical features. Objective: To develop a biomarker for Parkinson disease.
Background: There is experimental evidence of rifampicin inhibiting formation of α-synuclein fibrils, the neuropathologic hallmark of MSA. In a mouse model, there was improvement in behavior and neuropathological changes. Autonomic deficits occur typically early in human MSA with rapid progression, and are objectively quantifiable with standardized autonomic testing.
Methods: Twenty patients with Parkinson disease and 14 age and gender matched control subjects underwent examinations, autonomic testing and skin biopsies at the distal leg, distal thigh and proximal thigh. Skin biopsies were stained for PGP9.5, tyrosine hydroxylase, vasoactive intestinal peptide and α-synuclein. The density of intra-epidermal, sudomotor and pilomotor nerve fibers was calculated and the ratio of α-synuclein to nerve innervation (α-synuclein ratio). Results were compared to exam scores and autonomic function testing.
Methods: We undertook an oligocenter, randomized, double-blind, placebo-controlled trial of rifampicin in MSA (n = 100) and followed
Results: Patients with Parkinson disease had a distal sensory and autonomic neuropathy characterized by loss of intra-epidermal and
28
Abstracts / Autonomic Neuroscience: Basic and Clinical 177 (2013) 1–65
pilomotor fibers (P b 0.05 vs. controls, all sites) but no difference in sudomotor innervation. Patients with Parkinson disease had higher αsynuclein ratios compared to controls within pilomotor nerves and sudomotor nerves at all sites (P b 0.01, all sites). Higher α-synuclein ratios correlated with the fall in systolic blood pressure on tilt (r = -0.55, P b 0.01), the Hoehn and Yahr scores (r = 0.38, P b 0.05) and with heart rate variability during paced breathing (r = -0.65, P N 0.01). Alphasynuclein ratios were not increased within sensory nerve fibers. Discussion: Alpha-synuclein ratios are elevated within sympathetic adrenergic and sympathetic cholinergic fibers, but not sensory fibers, of patients with Parkinson disease. Higher α-synuclein ratios are associated with greater autonomic dysfunction and more advanced Parkinson disease. These data suggest that the α-synuclein ratio may be a useful biomarker in patients with Parkinson disease. Acknowledgement: Study supported by NIH NINDS K23NS050209 (CHG), the Langer Family Foundation and the RJG Foundation (CHG). doi:10.1016/j.autneu.2013.05.037
Abstract 8.1 Sensory signaling in the enteric nervous system G. Mazzuoli (Department of Human Biology, TU München, Germany) The gastrointestinal tract is able to control and regulate all its functions independently from the central nervous system (CNS). This is achieved via the enteric nervous system (ENS), a network of neurons located inside the gut wall, which is capable to sense, transduce and respond to chemical and mechanical stimuli. Similar to the CNS classification, ENS neurons have been categorized as sensory, inter or motor-neurons. The concepts on enteric sensory neurons have been a matter of debate for many years. While some exclude the presence of enteric sensory neurons, committing this role to extrinsic afferents; others propose highly specialized enteric sensory neurons with particular characteristics. Recently, another concept has been put forward by different groups which suggest the existence of multifunctional enteric neurons. These neurons respond to mechanical stimulation but belong to neurochemically, electrophysiologically and functionally different classes, at least when using the hitherto established criteria. Thus it has been shown that interneurons and even motor neurons directly respond to mechanical stimulation. We recently validated this concept across different species and gut regions. Combining all evidences for sensory enteric neurons, it seems that a much higher number of enteric neurons than previously thought possess mechanosensitive properties. It will remain a challenge to incorporate the new concept on multifunctional enteric neurons into reflex circuits regulation gut behavior. doi:10.1016/j.autneu.2013.05.038
Abstract 8.2 Extrinsic Sensory Signalling – from Molecules to Drugs D. Grundy (Department of Biomedical Science, The University of Sheffield, Sheffield, S10 2TN, UK) One of the hallmarks of IBS is visceral hypersensitivity. Understanding the molecular basis of hypersensitivity therefore offers a rationale for novel therapeutics aimed at treating pain and discomfort. A subset of patients report the onset of their IBS symptoms to a
bout of gastroenteritis – so called post-infectious IBS, thus implicating an inflammatory trigger for hypersensitivity. We have developed an animal model to explore the link between gut immune activation and the long-term changes in sensory signalling that underlie visceral hypersensitivity. Our model utilizes an intestinal nematode Trichinella spiralis, which triggers a transient inflammatory response, that resolves spontaneously following worm expulsion. Post-infection we observe a persistent hypersensitivity to distension which we monitor using electrophysiological techniques that distinguish between altered excitability arising from phenotypic changes in ion channels expressed on sensory neurones and peripheral changes in the chemical milieu that influences sensory signal transduction via ligand-gated ion channels are receptors. These changes contribute to peripheral sensitization and represent potential targets for treatment. These targets can be validated using pharmacological tools which modulate ion channels and receptors or by the use of mouse transgenics to identify pivotal components in neuro-immune interactions. These point towards a critical role for mast cells and macrophages in modulating sensory signalling but there are issues around translation that have impact on drug discovery efforts. Nevertheless, key components of these neuro-immune interactions correlate with studies using patient biopsies, which reflect changes in the intestinal milieu as a disease biomarker and moreover offer mechanistic understanding of pain signalling in IBS. doi:10.1016/j.autneu.2013.05.039
Abstract 8.3 Central processing of visceral sensory signals L. Van Oudenhove (Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Belgium) The ‘brain-gut axis’, conceptualized as the bidirectional neurohumoral signaling system connecting the gastrointestinal tract with the central nervous system, is part of an integrated interoceptive system which is continuously signaling homeostatic information about the physiological condition of the body to the brain. At brain level, this homeostaticinteroceptive information is integrated with exteroceptive signals, input from the reward system (assessing the motivational/hedonic value of stimuli) and affective & cognitive brain circuits. Dysfunction of gut-brain signaling plays a major role in the generation of unexplained visceral pain as well as food intake disorders. In health, food digestion and absorption remains largely unperceived; only the small fraction of interoceptive gutbrain signals that requires a behavioural response (pain, hunger) reaches consciousness. Profound changes in gut-brain signaling, most notably plasma levels of (an)orexigenic gut peptides, follow the cycles of hunger and food intake. Together with neural pathways signaling gastric distension and digestion of nutrients, these are critical players in homeostatic gut-brain signaling controlling feeding behaviour. Abnormalities in these mechanisms, including inappropriate peripheral signaling and dysfunction of homeostatic (hypothalamus, brainstem, insula), reward (ventral tegmentum, striatum) or affective & cognitive [amygdala, prefrontal cortex (PFC) and anterior cingulate cortex (ACC)] circuits in the brain, may result in dysregulation of food intake. Similarly, visceral pain results from the conscious perception of gut-brain signaling induced by noxious stimuli. At brain level, visceral pain-related interoceptive signals are processed in homeostatic centers and integrated with and modulated by signals from reward, affective and cognitive neurocircuits. The latter project in a ‘top-down’ fashion to brainstem areas such as the periaqueductal gray, which in turn send descending projections to the dorsal horn of the spinal cord, where pain transmission is modulated (descending modulatory system). Dysfunction of this system may cause
Anderson (Department of Anatomy and Neuroscience, The University of Melbourne, VIC 3010 Australia) We compared in vivo cell cycle dynamics of developing thoracic dorsal root ganglia (DRG) and sympathetic stellate ganglia (StG). We used Sox10-immunohistochemistry to mark neural crest cells (NCCs) and glial cells and Tuj1 to mark neuroblasts and neurons. In the DRG, from E9.5-E11.5, the proportion of cycling cells (the growth fraction, GF) for NCCs (Sox10+ cells) is 100%, the cell cycle length (Tc) is short (~10 h) and S-phase (Ts) accounts for ~65% of the Tc. This ratio of Ts/Tc is maintained up until E13.5 when Tc dramatically increases and Ts shortens. This corresponds to when the first Sox10+ cells withdraw from the cell cycle. The first DRG neurons, marked by expression of Tuj1, appear between E9.5 and E10.5 as they withdraw permanently from the cell cycle. In the StG at E9.5, division of Sox10+ NCCs is rapid (Tc = 10.6 h) with a relatively long Ts. At E10.5, Sox10+ cells lengthened their Tc to 38 h and the Ts decreased. The first StG neuroblasts (Tuj1+ cells) appear on E10.5 and immediately exit the cell cycle, only to re-enter the cell cycle one day later at E11.5, when N80% of cells in the StG were Tuj1+ neuroblasts. Tuj1+ neuroblasts continued to cycle, with the first neuroblasts withdrawing permanently from the cell cycle after E12.5. While the pattern of proliferation was quite different in the two ganglia, with StG neuroblasts re-entering the cell cycle and continuing to proliferate rapidly after differentiation while DRG neurons permanently withdraw from the cell cycle on differentiation, in both tissues major changes in patterns of proliferation were marked by dramatic changes in cell cycle dynamics. This is consistent with the idea that significant changes in cell cycle parameters can alter the time available for signals to effect changes in cell behaviour.
27
patients for 12 months. Patients were randomized to rifampicin 300 mg twice daily or matching placebo. The primary outcome measure was the rate of change from baseline to 12 months in UMSARS I. Other outcome measures included the rate of change in UMSARS II and in total UMSARS (I + II), and change in autonomic symptoms (COMPASS_select). In addition, patients recruited at the Mayo site (n = 19) also underwent standardized autonomic testing in addition to clinical and laboratory evaluations at baseline and study completion. Sudomotor, cardiovagal, and adrenergic deficits were quantified on a composite autonomic severity scale (CASS, range 0-10). Thermoregulatory sweat test was performed to derive anterior body anhidrosis (TST%, 0-100). Results: Patients had possible (48%) or probable (52%) MSA; 38% were women. The mean age was 61.0 ± 8.5 (mean ± SD); 11 subjects withdrew prematurely. The study was stopped after pre-planned interim analysis met futility criteria. UMSARS I slopes were 0.50 ± 0.50 and 0.50 ± 0.70 in the placebo and rifampicin arms, respectively (P = 0.817). UMSARS II and total UMSARS slopes and the change in COMPASS_select were also not significantly different. Of the patients enrolled at Mayo, 10 received rifampicin, 9 placebo. CASS was 6.5 ± 2.8 versus 6.4 ± 2.3 at baseline and 7.2 ± 2.7 versus 6.9 ± 2.0 following treatment (rifampicin versus placebo, change p = 0.96). TST% was 31.4 ± 30.5 versus 48.4 ± 32.5 at baseline and 34.7 ± 27.6 versus 53.8 ± 38.6 following treatment (change p = 0.44). Conclusions: There was no significant effect of rifampicin in MSA, neither on the progression of clinical parameters, nor on progression of autonomic symptoms and deficits. Supported by NIH (P01NS44233, U54NS065736, K23NS075141, UL1RR24150) and Mayo Funds.
doi:10.1016/j.autneu.2013.05.035
doi:10.1016/j.autneu.2013.05.036
Abstract 7.4
Abstract 7.5
Randomized Trial of Rifampicin in MSA: Primary Outcomes and Effect on Autonomic Function
Cutaneous α-synuclein and Parkinson Disease, a biomarker of disease severity
W. Singer (Mayo Clinic, Rochester, MN, United States), D. Robertson (Vanderbilt University, Nashville, TN, United States), S. Gilman (University of Michigan, Ann Arbor, MI, United States), H. Kaufmann (New York University Medical Center, New York, NY, United States), I. Biaggioni (Vanderbilt University, Nashville, TN, United States), R. Freeman (Beth Israel Medical Center, Boston, MA, United States), R.D. Fealey, J. Mandrekar (Mayo Clinic, Rochester, MN, United States), W. Dupont (Vanderbilt University, Nashville, TN, United States), T.L. Gehrking, J.D. Schmelzer, D.M. Sletten, J.A. Gehrking, P.A. Low (Mayo Clinic, Rochester, MN, United States)
Ningshan Wang, Christopher H. Gibbons, Roy Freeman (Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA)
Objective: To determine the effect of rifampicin on clinical progression and progression of autonomic failure in multiple system atrophy (MSA).
Background: Parkinson disease is a multisystem neurodegenerative disease with deposition of α-synuclein in the central, peripheral and enteric nervous systems. The most prominent manifestations of Parkinson disease are due to central, motor system neurodegeneration but there is also widespread peripheral, autonomic and enteric nervous system degeneration with associated clinical features. Objective: To develop a biomarker for Parkinson disease.
Background: There is experimental evidence of rifampicin inhibiting formation of α-synuclein fibrils, the neuropathologic hallmark of MSA. In a mouse model, there was improvement in behavior and neuropathological changes. Autonomic deficits occur typically early in human MSA with rapid progression, and are objectively quantifiable with standardized autonomic testing.
Methods: Twenty patients with Parkinson disease and 14 age and gender matched control subjects underwent examinations, autonomic testing and skin biopsies at the distal leg, distal thigh and proximal thigh. Skin biopsies were stained for PGP9.5, tyrosine hydroxylase, vasoactive intestinal peptide and α-synuclein. The density of intra-epidermal, sudomotor and pilomotor nerve fibers was calculated and the ratio of α-synuclein to nerve innervation (α-synuclein ratio). Results were compared to exam scores and autonomic function testing.
Methods: We undertook an oligocenter, randomized, double-blind, placebo-controlled trial of rifampicin in MSA (n = 100) and followed
Results: Patients with Parkinson disease had a distal sensory and autonomic neuropathy characterized by loss of intra-epidermal and
28
Abstracts / Autonomic Neuroscience: Basic and Clinical 177 (2013) 1–65
pilomotor fibers (P b 0.05 vs. controls, all sites) but no difference in sudomotor innervation. Patients with Parkinson disease had higher αsynuclein ratios compared to controls within pilomotor nerves and sudomotor nerves at all sites (P b 0.01, all sites). Higher α-synuclein ratios correlated with the fall in systolic blood pressure on tilt (r = -0.55, P b 0.01), the Hoehn and Yahr scores (r = 0.38, P b 0.05) and with heart rate variability during paced breathing (r = -0.65, P N 0.01). Alphasynuclein ratios were not increased within sensory nerve fibers. Discussion: Alpha-synuclein ratios are elevated within sympathetic adrenergic and sympathetic cholinergic fibers, but not sensory fibers, of patients with Parkinson disease. Higher α-synuclein ratios are associated with greater autonomic dysfunction and more advanced Parkinson disease. These data suggest that the α-synuclein ratio may be a useful biomarker in patients with Parkinson disease. Acknowledgement: Study supported by NIH NINDS K23NS050209 (CHG), the Langer Family Foundation and the RJG Foundation (CHG). doi:10.1016/j.autneu.2013.05.037
Abstract 8.1 Sensory signaling in the enteric nervous system G. Mazzuoli (Department of Human Biology, TU München, Germany) The gastrointestinal tract is able to control and regulate all its functions independently from the central nervous system (CNS). This is achieved via the enteric nervous system (ENS), a network of neurons located inside the gut wall, which is capable to sense, transduce and respond to chemical and mechanical stimuli. Similar to the CNS classification, ENS neurons have been categorized as sensory, inter or motor-neurons. The concepts on enteric sensory neurons have been a matter of debate for many years. While some exclude the presence of enteric sensory neurons, committing this role to extrinsic afferents; others propose highly specialized enteric sensory neurons with particular characteristics. Recently, another concept has been put forward by different groups which suggest the existence of multifunctional enteric neurons. These neurons respond to mechanical stimulation but belong to neurochemically, electrophysiologically and functionally different classes, at least when using the hitherto established criteria. Thus it has been shown that interneurons and even motor neurons directly respond to mechanical stimulation. We recently validated this concept across different species and gut regions. Combining all evidences for sensory enteric neurons, it seems that a much higher number of enteric neurons than previously thought possess mechanosensitive properties. It will remain a challenge to incorporate the new concept on multifunctional enteric neurons into reflex circuits regulation gut behavior. doi:10.1016/j.autneu.2013.05.038
Abstract 8.2 Extrinsic Sensory Signalling – from Molecules to Drugs D. Grundy (Department of Biomedical Science, The University of Sheffield, Sheffield, S10 2TN, UK) One of the hallmarks of IBS is visceral hypersensitivity. Understanding the molecular basis of hypersensitivity therefore offers a rationale for novel therapeutics aimed at treating pain and discomfort. A subset of patients report the onset of their IBS symptoms to a
bout of gastroenteritis – so called post-infectious IBS, thus implicating an inflammatory trigger for hypersensitivity. We have developed an animal model to explore the link between gut immune activation and the long-term changes in sensory signalling that underlie visceral hypersensitivity. Our model utilizes an intestinal nematode Trichinella spiralis, which triggers a transient inflammatory response, that resolves spontaneously following worm expulsion. Post-infection we observe a persistent hypersensitivity to distension which we monitor using electrophysiological techniques that distinguish between altered excitability arising from phenotypic changes in ion channels expressed on sensory neurones and peripheral changes in the chemical milieu that influences sensory signal transduction via ligand-gated ion channels are receptors. These changes contribute to peripheral sensitization and represent potential targets for treatment. These targets can be validated using pharmacological tools which modulate ion channels and receptors or by the use of mouse transgenics to identify pivotal components in neuro-immune interactions. These point towards a critical role for mast cells and macrophages in modulating sensory signalling but there are issues around translation that have impact on drug discovery efforts. Nevertheless, key components of these neuro-immune interactions correlate with studies using patient biopsies, which reflect changes in the intestinal milieu as a disease biomarker and moreover offer mechanistic understanding of pain signalling in IBS. doi:10.1016/j.autneu.2013.05.039
Abstract 8.3 Central processing of visceral sensory signals L. Van Oudenhove (Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Belgium) The ‘brain-gut axis’, conceptualized as the bidirectional neurohumoral signaling system connecting the gastrointestinal tract with the central nervous system, is part of an integrated interoceptive system which is continuously signaling homeostatic information about the physiological condition of the body to the brain. At brain level, this homeostaticinteroceptive information is integrated with exteroceptive signals, input from the reward system (assessing the motivational/hedonic value of stimuli) and affective & cognitive brain circuits. Dysfunction of gut-brain signaling plays a major role in the generation of unexplained visceral pain as well as food intake disorders. In health, food digestion and absorption remains largely unperceived; only the small fraction of interoceptive gutbrain signals that requires a behavioural response (pain, hunger) reaches consciousness. Profound changes in gut-brain signaling, most notably plasma levels of (an)orexigenic gut peptides, follow the cycles of hunger and food intake. Together with neural pathways signaling gastric distension and digestion of nutrients, these are critical players in homeostatic gut-brain signaling controlling feeding behaviour. Abnormalities in these mechanisms, including inappropriate peripheral signaling and dysfunction of homeostatic (hypothalamus, brainstem, insula), reward (ventral tegmentum, striatum) or affective & cognitive [amygdala, prefrontal cortex (PFC) and anterior cingulate cortex (ACC)] circuits in the brain, may result in dysregulation of food intake. Similarly, visceral pain results from the conscious perception of gut-brain signaling induced by noxious stimuli. At brain level, visceral pain-related interoceptive signals are processed in homeostatic centers and integrated with and modulated by signals from reward, affective and cognitive neurocircuits. The latter project in a ‘top-down’ fashion to brainstem areas such as the periaqueductal gray, which in turn send descending projections to the dorsal horn of the spinal cord, where pain transmission is modulated (descending modulatory system). Dysfunction of this system may cause