Periaqueductal Gray Region Research Articles

The involvement of the pathway connecting the substantia nigra, the periaqueductal gray matter and the retrotrapezoid nucleus in breathing control in a rat model of Parkinson's disease

Parkinson's disease (PD) is characterized by a reduction in the number of dopaminergic neurons of the substantia nigra (SNpc), accompanied by motor and non-motor deficiencies such as respiratory failure. Here, our aim was to investigate possible neuronal communications between the SNpc and chemoreceptor neurons within the retrotrapezoid nucleus (RTN), in order to explain neurodegeneration and the loss of breathing function in the 6-OHDA PD animal model. Male Wistar rats received tracer injections in the SNpc, RTN and periaqueductal gray (PAG) regions to investigate the projections between those regions. The results showed that neurons of the SNpc project to the RTN by an indirect pathway that goes through the PAG region. In different groups of rats, reductions in the density of neuronal markers (NeuN) and the number of catecholaminergic varicosities in PAG, as well as reductions in the number of CO2-activated PAG neurons with RTN projections, were observed in a 6-OHDA model of PD. Physiological experiments showed that inhibition of the PAG by bilateral injection of muscimol did not produce resting breathing disturbances but instead reduced genioglossus (GGEMG) and abdominal (AbdEMG) muscle activity amplitude induced by hypercapnia in control rats that were urethane-anesthetized, vagotomized, and artificially ventilated. However, in a model of PD, we found reductions in resting diaphragm muscle activity (DiaEMG) and GGEMG frequencies, as well as in hypercapnia-induced DiaEMG, GGEMG and AbdEMG frequencies and GGEMG and AbdEMG amplitudes. Therefore, we can conclude that there is an indirect pathway between neurons of the SNpc and RTN that goes through the PAG and that there is a defect of this pathway in an animal model of PD.

Intercollicular nucleus electric stimulation encoded “walk forward” commands in pigeons

Abstract The bio-robot research field is growing. Robo-pigeons have been successfully programmed to turn left or right; however, a satisfactory method of commanding a robo-pigeon to walk forward is still lacking. This problem has become a roadblock to progress in bio-robot research and applications. In mammals, the midbrain periaqueductal gray region (PAG) plays a key role in mediating defensive reactions in response to fear and anxiety. The avian intercollicular nucleus (ICo) is thought to correspond to the PAG. In this study, we found that microstimulating the ICo could successfully induce a robo-pigeon to walk forward. Compared with stimulation of the previously used archistriatum, the response time was considerably shorter and the behavior accuracy significantly higher. This paper describes in detail the process of controlling a robo-pigeon such that it walks forward and backward along a prescribed straight line. From the results, we draw the conclusion that the ICo is suitable for prompting the “walk forward” order in robo-pigeons.

Disrupted functional connectivity between the periaqueductal gray and other brain regions in a rat model of recurrent headache

Functional connectivity (FC) has been used to investigate the pathophysiology of migraine. We aimed to identify atypical FC between the periaqueductal gray (PAG) and other brain areas in rats induced by repeated meningeal nociception. The rat model was established by infusing an inflammatory soup (IS) through supradural catheters in conscious rats. Quiescent and face-grooming behaviors were observed to assess nociceptive behavior. FC analysis seeded on the PAG was performed on rats 21 days after IS infusion. The rats exhibited nociceptive behavior correlates of human behaviors associated with migraine after IS infusion. The PAG showed increased FC with the prefrontal cortex, cingulate gyrus, and motor cortex but decreased FC with the basal ganglia, dorsal lateral thalamus, internal capsule and prelimbic cortex in the rat model. The atypical FC of the PAG with brain regions in the rat model that are involved in nociception, somatosensory processing, emotional processing, and pain modulation are consistent with the clinical data from migraineurs, indicate that resting-state FC changes in migraine patients may be a consequence of headache attacks, and further validate this rat model of chronic migraine.

Repeated threat (without direct harm) alters metabolic capacity in select regions that drive defensive behavior

To understand the behavioral consequences of intermittent anticipatory stress resulting from threats without accompanying physiological challenges, we developed a semi-naturalistic rodent housing and foraging environment that can include threats that are unpredictable in timing. Behavior is automatically recorded while rats forage for food or water. Over three weeks, the threats have been shown to elicit risk assessment behaviors, increase defensive burying and increase adrenal gland weight. To identify brain regions activated by this manipulation, we measured cytochrome c oxidase (COX), which is tightly coupled to neural activity. Adolescent male Sprague–Dawley rats were randomly assigned to control (CT) or unpredictable threat/stress (ST) housing conditions consisting of two tub cages, one with food and another with water, separated by a tunnel. Over three weeks (P31–P52), the ST group received randomly timed (probability of 0.25), simultaneous presentations of ferret odor, an abrupt light, and sound at the center of the tunnel. The ST group had consistently fewer tunnel crossings than the CT group, but similar body weights. Group differences in COX activity were detected in regions implicated in the control of defensive burying. There was an increase in COX activity in the hypothalamic premammillary dorsal nucleus (PMD) and lateral septum (LS), whereas a decrease was observed in the periaqueductal gray (PAG) and CA3 region of the hippocampus. There were no significant differences in the anterior cingulate cortex, prefrontal cortex, striatum or motor cortex. The sites with changes in metabolic capacity are candidates for the sites of plasticity that may underlie the behavioral adaptations to intermittent threats.

Functional neuroanatomy in panic disorder: Status quo of the research

AIMTo provide an overview of the current research in the functional neuroanatomy of panic disorder.METHODSPanic disorder (PD) is a frequent psychiatric disease. Gorman et al (1989; 2000) proposed a comprehensive neuroanatomical model of PD, which suggested that fear- and anxiety-related responses are mediated by a so-called “fear network” which is centered in the amygdala and includes the hippocampus, thalamus, hypothalamus, periaqueductal gray region, locus coeruleus and other brainstem sites. We performed a systematic search by the electronic database PubMed. Thereby, the main focus was laid on recent neurofunctional, neurostructural, and neurochemical studies (from the period between January 2012 and April 2016). Within this frame, special attention was given to the emerging field of imaging genetics.RESULTSWe noted that many neuroimaging studies have reinforced the role of the “fear network” regions in the pathophysiology of panic disorder. However, recent functional studies suggest abnormal activation mainly in an extended fear network comprising brainstem, anterior and midcingulate cortex (ACC and MCC), insula, and lateral as well as medial parts of the prefrontal cortex. Interestingly, differences in the amygdala activation were not as consistently reported as one would predict from the hypothesis of Gorman et al (2000). Indeed, amygdala hyperactivation seems to strongly depend on stimuli and experimental paradigms, sample heterogeneity and size, as well as on limitations of neuroimaging techniques. Advanced neurochemical studies have substantiated the major role of serotonergic, noradrenergic and glutamatergic neurotransmission in the pathophysiology of PD. However, alterations of GABAergic function in PD are still a matter of debate and also their specificity remains questionable. A promising new research approach is “imaging genetics”. Imaging genetic studies are designed to evaluate the impact of genetic variations (polymorphisms) on cerebral function in regions critical for PD. Most recently, imaging genetic studies have not only confirmed the importance of serotonergic and noradrenergic transmission in the etiology of PD but also indicated the significance of neuropeptide S receptor, CRH receptor, human TransMEMbrane protein (TMEM123D), and amiloride-sensitive cation channel 2 (ACCN2) genes.CONCLUSIONIn light of these findings it is conceivable that in the near future this research will lead to the development of clinically useful tools like predictive biomarkers or novel treatment options.

Injection of Toll-like receptor 4 siRNA into the ventrolateral periaqueductal gray attenuates withdrawal syndrome in morphine-dependent rats.

We assessed the role of the Toll-like receptor 4 (TLR4) gene in the ventrolateral periaqueductal gray (vlPAG) region of morphine-dependent rats on attenuating withdrawal syndrome, and regulating glutamic acid decarboxylase (GAD67), glutamic acid (Glu), and gamma-aminobutyric acid (GABA). After siRNA-mediated downregulation of TLR4, changes were observed in withdrawal behavior and downstream signaling molecules. Rats were injected into the vlPAG with TLR4 siRNA, followed by intraperitoneal injection of morphine for 5 consecutive days, and then naloxone, and the behavioral indices of morphine withdrawal were observed. 'Wet-dog' shakes, teeth chattering, and the total scores of withdrawal reactions were reduced. TLR4 expression and Glu levels were reduced, whereas GAD67 and GABA levels were increased. Overall, these findings indicate that modifying TLR4 gene expression in the vlPAG stimulates expression of the downstream signaling molecule, GAD67, which decreases Glu levels and increases GABA levels. This mechanism may explain the inhibition of withdrawal syndrome in morphine-dependent rats.

Fatty-acid-binding protein inhibition produces analgesic effects through peripheral and central mechanisms.

BackgroundFatty-acid-binding proteins (FABPs) are intracellular carriers for endocannabinoids, N-acylethanolamines, and related lipids. Previous work indicates that systemically administered FABP5 inhibitors produce analgesia in models of inflammatory pain. It is currently not known whether FABP inhibitors exert their effects through peripheral or central mechanisms. Here, we examined FABP5 distribution in dorsal root ganglia and spinal cord and examined the analgesic effects of peripherally and centrally administered FABP5 inhibitors.ResultsImmunofluorescence revealed robust expression of FABP5 in lumbar dorsal root ganglia. FABP5 was distributed in peptidergic calcitonin gene-related peptide-expressing dorsal root ganglia and non-peptidergic isolectin B4-expressing dorsal root ganglia. In addition, the majority of dorsal root ganglia expressing FABP5 also expressed transient receptor potential vanilloid 1 (TRPV1) and peripherin, a marker of nociceptive fibers. Intraplantar administration of FABP5 inhibitors reduced thermal and mechanical hyperalgesia in the complete Freund’s adjuvant model of chronic inflammatory pain. In contrast to its robust expression in dorsal root ganglia, FABP5 was sparsely distributed in the lumbar spinal cord and intrathecal administration of FABP inhibitor did not confer analgesic effects. Administration of FABP inhibitor via the intracerebroventricular (i.c.v.) route reduced thermal hyperalgesia. Antagonists of peroxisome proliferator-activated receptor alpha blocked the analgesic effects of peripherally and i.c.v. administered FABP inhibitor while antagonism of cannabinoid receptor 1 blocked the effects of peripheral FABP inhibition and a TRPV1 antagonist blocked the effects of i.c.v. administered inhibitor. Although FABP5 and TRPV1 were co-expressed in the periaqueductal gray region of the brain, which is known to modulate pain, knockdown of FABP5 in the periaqueductal gray using adeno-associated viruses and pharmacological FABP5 inhibition did not produce analgesic effects.ConclusionsThis study demonstrates that FABP5 is highly expressed in nociceptive dorsal root ganglia neurons and FABP inhibitors exert peripheral and supraspinal analgesic effects. This indicates that peripherally restricted FABP inhibitors may serve as a new class of analgesic and anti-inflammatory agents.

Effect of melatonin injection into the periaqueductal gray on antinociception and tonic immobility in male rats

Melatonin (MLT) is a neurohormone with significant involvement in several biological functions, of which antinociception and tonic immobility (TI) may be the key neurobehavioral components to survive in adverse conditions such as a predator attack. TI-induced antinociception can be elicited, facilitated, or increased through opioid and γ-aminobutyric acid (GABA) among other chemical mediators at several levels of the central nervous system, mainly in the periaqueductal gray (PAG). The aim of this study was to assess the effect of the microinjection of MLT into the main PAG regions that are related to different integrated defensive responses, namely dorsal (D) and ventrolateral (VL), on both antinociception through the tail-flick (TF) test and TI duration as single behavioral response and on combined behavioral responses (TF/TI). We found that the microinjection of MLT into the main PAG areas produced antinociception but did not affect the TI duration. The microinjection of MLT into the D-PAG decreased TF latency during TI in the combined trial (TF/TI), which implies that TI-induced antinociception was blocked. The microinjection of MLT into the VL-PAG maintained the antinociceptive capability of the TI without addition or increase in the antinociceptive effects, implying a permissive effect by MLT on the TI-induced antinociception. MLT administration into the D-PAG decreased the TI duration on the TF/TI, whereas MLT administration into the VL-PAG had the opposite effect of significantly increasing TI duration with the TF/TI trial.

Nonspecific periaqueductal gray lesions on T2WI in episodic migraine.

BackgroundThe specific periaqueductal gray (PAG) lesions with migraine-like headache were easily identified on conventional MR images in clinical practice, and the aim of this study is to investigate the nonspecific periaqueductal gray (PAG) lesions in episodic migraine (EM) patients based on T2 weighted imaging (T2WI).MethodsT2WI images were obtained from 18 EM patients and 18 normal controls (NC) on 3.0 T MR system. The images were observed by two experienced radiologists, and the lesions were identified on T2WI by consensus by 2 experienced neuroradiologists blinded to the patient identity. Chi-Square test was performed for the significance test.ResultsRing-like hyperintensity lesions (HILs) around the PAG region were observed in 14 EM patients and in 5 NCs on T2WI. Four EM patients and 13 NCs were normal in PAG region. The significance was revealed by Chi-Square test (P = 0.003).ConclusionHIL of PAG may be the direct evidence of the EM genesis, and the further structural and functional study should be performed to elucidate the neuromechanism of migraine pathogenesis.

The organization of defensive behavior elicited by optogenetic excitation of rat lateral or ventrolateral periaqueductal gray.

Rodents display characteristic defense responses to predators that are influenced by predatory imminence. The midbrain periaqueductal gray (PAG) serves an important role controlling these responses. The most influential model states that variations in defensive topography are due to distinct PAG regions: ventrolateral PAG (VLPAG) controls postencounter defense, such as freezing and immobility, whereas lateral PAG (LPAG) controls circa-strike defense, such as escape and flight. Here we used channel rhodopsin (ChR2) stimulation to probe the structure of defensive behavior controlled by LPAG and VLPAG. Suprathreshold LPAG stimulation evoked circa-strike defense that was replaced by freezing at stimulation offset. Suprathreshold VLPAG stimulation evoked postencounter--freezing and immobility--but never circa-strike defense. More interestingly, the topography of defensive behavior evoked from LPAG scaled with variations in 465 nm light power. As light power increased, LPAG animals expressed the full defensive syntax of freezing then activity then flight characteristic of increasing predatory imminence. In contrast, the frequency, not topography, of defensive behavior evoked from VLPAG scaled with variations in light power. These findings suggest that LPAG and VLPAG can control variations in defense with increasing predatory imminence in 2 ways. First, consistent with past models, topographical variation can be assembled from different defensive responses controlled by the LPAG (circa-strike) and VLPAG (postencounter). Second, topographical variation can be assembled from variations in LPAG activity itself. (PsycINFO Database Record

The mesencephalic GCt-ICo complex and tonic immobility in pigeons (Columba livia): a c-Fos study.

Tonic immobility (TI) is a response to a predator attack, or other inescapable danger, characterized by immobility, analgesia and unresponsiveness to external stimuli. In mammals, the periaqueductal gray (PAG) and deep tectal regions control the expression of TI as well as other defensive behaviors. In birds, little is known about the mesencephalic circuitry involved in the control of TI. Here, adult pigeons (both sex, n=4/group), randomly assigned to non-handled, handled or TI groups, were killed 90min after manipulations and the brains processed for detection of c-Fos immunoreactive cells (c-Fos-ir, marker for neural activity) in the mesencephalic central gray (GCt) and the adjacent nucleus intercollicularis (ICo). The NADPH-diaphorase staining delineated the boundaries of the sub nuclei in the ICo-GCt complex. Compared to non-handled, TI (but not handling) induced c-Fos-ir in NADPH-diaphorase-rich and -poor regions. After TI, the number of c-Fos-ir increased in the caudal and intermediate areas of the ICo (but not in the GCt), throughout the rostrocaudal axis of the dorsal stratum griseum periventriculare (SGPd) of the optic tectum and in the n. mesencephalicus lateralis pars dorsalis (MLd), which is part of the ascending auditory pathway. These data suggest that inescapable threatening stimuli such as TI may recruit neurons in discrete areas of ICo-GCt complex, deep tectal layer and in ascending auditory circuits that may control the expression of defensive behaviors in pigeons. Additionally, data indicate that the contiguous deep tectal SCPd (but not GCt) in birds may be functionally comparable to the mammalian dorsal PAG.

Tuning the brain for motherhood: prolactin-like central signalling in virgin, pregnant, and lactating female mice.

Prolactin is fundamental for the expression of maternal behaviour. In virgin female rats, prolactin administered upon steroid hormone priming accelerates the onset of maternal care. By contrast, the role of prolactin in mice maternal behaviour remains unclear. This study aims at characterizing central prolactin activity patterns in female mice and their variation through pregnancy and lactation. This was revealed by immunoreactivity of phosphorylated (active) signal transducer and activator of transcription 5 (pSTAT5-ir), a key molecule in the signalling cascade of prolactin receptors. We also evaluated non-hypophyseal lactogenic activity during pregnancy by administering bromocriptine, which suppresses hypophyseal prolactin release. Late-pregnant and lactating females showed significantly increased pSTAT5-ir resulting in a widespread pattern of immunostaining with minor variations between pregnant and lactating animals, which comprises nuclei of the sociosexual and maternal brain, including telencephalic (septum, nucleus of the stria terminalis, and amygdala), hypothalamic (preoptic, paraventricular, supraoptic, and ventromedial), and midbrain (periaqueductal grey) regions. During late pregnancy, this pattern was not affected by the administration of bromocriptine, suggesting it to be elicited mostly by non-hypophyseal lactogenic agents, likely placental lactogens. Virgin females displayed, instead, a variable pattern of pSTAT5-ir restricted to a subset of the brain nuclei labelled in pregnant and lactating mice. A hormonal substitution experiment confirmed that estradiol and progesterone contribute to the variability found in virgin females. Our results reflect how the shaping of the maternal brain takes place prior to parturition and suggest that lactogenic agents are important candidates in the development of maternal behaviours already during pregnancy.

Pain modulation is affected differently in medication-overuse headache and chronic myofascial pain - A multimodal MRI study.

Background Neuroimaging studies revealed structural and functional changes in medication-overuse headache (MOH), but it remains unclear whether similar changes could be observed in other chronic pain disorders. Methods In this cross-sectional study, we investigated functional connectivity (FC) with resting-state functional magnetic resonance imaging (fMRI) and white matter integrity using diffusion tensor imaging (DTI) to measure fractional anisotropy (FA) and mean diffusivity (MD) in patients with MOH ( N = 12) relative to two control groups: patients with chronic myofascial pain (MYO; N = 11) and healthy controls (CN; N = 16). Results In a data-driven approach we found hypoconnectivity in the fronto-parietal attention network in both pain groups relative to CN (i.e. MOH < CN and MYO < CN). In contrast, hyperconnectivity in the saliency network (SN) was detected only in MOH, which correlated with FA in the insula. In a seed-based analysis we investigated FC between the periaqueductal grey (PAG) and all other brain regions. In addition to overlapping hyperconnectivity seen in patient groups (relative to CN), MOH had a distinct connectivity pattern with lower FC to parieto-occipital regions and higher FC to orbitofrontal regions compared to controls. FA and MD abnormalities were mostly observed in MOH, involving the insula. Conclusions Hyperconnectivity within the SN along with associated white matter changes therein suggest a particular role of this network in MOH. In addition, abnormal connectivity between the PAG and other pain modulatory (frontal) regions in MOH are consistent with dysfunctional central pain control.

The initial fall in arterial pressure evoked by endotoxin is mediated by the ventrolateral periaqueductal gray.

This study tested the hypothesis that the initial fall in arterial pressure evoked by lipopolysaccharide (LPS) is mediated by the ventrolateral column of the midbrain periaqueductal gray region (vlPAG). To test this hypothesis, the local anaesthetic lidocaine (2%; 0.1μL, 0.2μL or 1.0μL), the delta opioid receptor antagonist naltrindole (2nmol) or saline was microinjected into the vlPAG of isoflurane-anaesthetized rats bilaterally and LPS (1mg/kg) or saline was administered intravenously 2min later. Both lidocaine and naltrindole inhibited LPS-evoked hypotension significantly but did not affect arterial pressure in saline-treated control animals. Neither lidocaine nor naltrindole altered heart rate significantly in either LPS-treated or control animals. Microinjection of lidocaine or naltrindole into the dorsolateral PAG was ineffective. These data indicate that the vlPAG plays an important role in the initiation of endotoxic hypotension and further show that delta opioid receptors in the vlPAG participate in the response.

FMRI of spinal and supra-spinal correlates of temporal pain summation in fibromyalgia patients.

Fibromyalgia syndrome (FM) is a debilitating chronic pain condition, which afflicts primarily females. Although the etiology of this illness is not completely understood, FM pain is thought to rely on enhanced pain sensitivity maintained by central mechanisms. One of these mechanisms is central pain amplification, which is characterized by altered temporal summation of second pain (TSSP). Here we use a TSSP paradigm and functional MRI (fMRI) of the spinal cord, brainstem, and brain to noninvasively examine the central nervous system contributions to TSSP in FM patients and normal controls (NC). Functional MRI of pain-free female adults (N = 15) and FM patients (N = 14) was conducted while brief, repetitive heat pain stimuli (0.33 Hz) were applied to the thenar eminence of the hand (C6 dermatome). The stimulus intensity was adjusted to each participant's heat pain sensitivity to achieve moderate pain. Data were analyzed by means of a General Linear Model and region-of-interest analyses. All participants demonstrated significant pain summation in the TSSP condition. FM subjects, however, required significantly lower stimulus intensities than NC to achieve similar TSSP. fMRI analyses of perceptually equal TSSP identified similar brain activity in NC and FM subjects; however, multiple areas in the brainstem (rostral ventromedial medulla and periaqueductal grey region) and spinal cord (dorsal horn) exhibited greater activity in NC subjects. Finally, increased after-sensations and enhanced dorsal horn activity was demonstrated in FM patients. In conclusion, the spinal and brainstem BOLD responses to TSSP are different between NC and FM patients, which may indicate alterations to descending pain control mechanisms suggesting contributions of these mechanisms to central sensitization and pain of FM patients.

Recruitment of dorsal midbrain catecholaminergic pathways in the recovery from nerve injury evoked disabilities.

BackgroundThe periaqueductal gray region (PAG) is one of several brain areas identified to be vulnerable to structural and functional change following peripheral nerve injury. Sciatic nerve constriction injury (CCI) triggers neuropathic pain and three distinct profiles of changes in complex behaviours, which include altered social and sleep–wake behaviours as well as changes in endocrine function. The PAG encompasses subgroups of the A10 dopaminergic and A6 noradrenergic cell groups; the origins of significant ascending projections to hypothalamic and forebrain regions, which regulate sleep, complex behaviours and endocrine function. We used RT-PCR, western blots and immunohistochemistry for tyrosine hydroxylase to determine whether (1) tyrosine hydroxylase increased in the A10/A6 cells and/or; (2) de novo synthesis of tyrosine hydroxylase, in a ‘TH-naïve’ population of ventral PAG neurons characterized rats with distinct patterns of behavioural and endocrine change co-morbid with CCI evoked-pain.ResultsEvidence for increased tyrosine hydroxylase transcription and translation in the constitutive A10/A6 cells was found in the midbrain of rats that showed an initial 2–3 day post-CCI, behavioural and endocrine change, which recovered by days 5–6 post-CCI. Furthermore these rats showed significant increases in the density of TH-IR fibres in the vPAG.ConclusionsOur data provide evidence for: (1) potential increases in dopamine and noradrenaline synthesis in vPAG cells; and (2) increased catecholaminergic drive on vPAG neurons in rats in which transient changes in social behavior are seen following CCI. The data suggests a role for dopaminergic and noradrenergic outputs, and catecholaminergic inputs of the vPAG in the expression of one of the profiles of behavioural and endocrine change triggered by nerve injury.

Failure of hippocampal deactivation during loss events in treatment-resistant depression.

Major depressive disorder is characterized by anhedonia, cognitive biases, ruminations, hopelessness and increased anxiety. Blunted responses to rewards have been reported in a number of recent neuroimaging and behavioural studies of major depressive disorder. In contrast, neural responses to aversive events remain an under-studied area. While selective serotonergic reuptake inhibitors are often effective in treating major depressive disorder, their mechanism of action remains unclear. Following a series of animal model investigations of depressive illness and serotonergic function, Deakin and Graeff predicted that brain activity in patients with major depressive disorder is associated with an overactive dorsal raphe nucleus with overactive projections to the amygdala, periaqueductal grey and striatum, and an underactive median raphe nucleus with underactive projections to the hippocampus. Here we describe an instrumental loss-avoidance and win-gain reinforcement learning functional magnetic resonance imaging study with 40 patients with highly treatment-resistant major depressive disorder and never-depressed controls. The dorsal raphe nucleus/ periaqueductal grey region of the midbrain and hippocampus were found to be overactive in major depressive disorder during unsuccessful loss-avoidance although the median raphe nucleus was not found to be underactive. Hippocampal overactivity was due to a failure to deactivate during loss events in comparison to controls, and hippocampal over-activity correlated with depression severity, self-report 'hopelessness' and anxiety. Deakin and Graeff argued that the median raphe nucleus normally acts to inhibit consolidation of aversive memories via the hippocampus and this system is underactive in major depressive disorder, facilitating the development of ruminations, while the dorsal raphe nucleus system is engaged by distal cues predictive of threats and is overactive in major depressive disorder. During win events the striatum was underactive in major depressive disorder. We tested individual patient consistency of these findings using within-study replication. Abnormal hippocampal activity correctly predicted individual patient diagnostic status in 97% (sensitivity 95%, specificity 100%) of subjects, and abnormal striatal activity predicted diagnostic status in 84% (sensitivity 79%, specificity 89%) of subjects. We conclude that the neuroimaging findings were largely consistent with Deaken and Graeff's predictions, abnormally increased hippocampal activity during loss events was an especially consistent abnormality, and brainstem serotonergic nuclei merit further study in depressive illness.

Interdisciplinary approaches of transcranial magnetic stimulation applied to a respiratory neuronal circuitry model.

Respiratory related diseases associated with the neuronal control of breathing represent life-threatening issues and to date, no effective therapeutics are available to enhance the impaired function. The aim of this study was to determine whether a preclinical respiratory model could be used for further studies to develop a non-invasive therapeutic tool applied to rat diaphragmatic neuronal circuitry. Transcranial magnetic stimulation (TMS) was performed on adult male Sprague-Dawley rats using a human figure-of-eight coil. The largest diaphragmatic motor evoked potentials (MEPdia) were recorded when the center of the coil was positioned 6 mm caudal from Bregma, involving a stimulation of respiratory supraspinal pathways. Magnetic shielding of the coil with mu metal reduced magnetic field intensities and improved focality with increased motor threshold and lower amplitude recruitment curve. Moreover, transynaptic neuroanatomical tracing with pseudorabies virus (applied to the diaphragm) suggest that connections exist between the motor cortex, the periaqueductal grey cell regions, several brainstem neurons and spinal phrenic motoneurons (distributed in the C3-4 spinal cord). These results reveal the anatomical substrate through which supraspinal stimulation can convey descending action potential volleys to the spinal motoneurons (directly or indirectly). We conclude that MEPdia following a single pulse of TMS can be successfully recorded in the rat and may be used in the assessment of respiratory supraspinal plasticity. Supraspinal non-invasive stimulations aimed to neuromodulate respiratory circuitry will enable new avenues of research into neuroplasticity and the development of therapies for respiratory dysfunction associated with neural injury and disease (e.g. spinal cord injury, amyotrophic lateral sclerosis).

The role of the descending inhibitory pain mechanism in musculoskeletal pain following high-velocity, low amplitude thrust manipulation: a review of the literature.

Although the antinociceptive effect of high-velocity, low amplitude thrust manipulation (HVLAM) has been recognized by numerous systematic reviews, the underlying mechanism for manipulation-related pain relief remains poorly understood. An increasing number of studies have explored its analgesic mechanism suggesting that the excitation of the descending inhibitory pain mechanism (DIPM) might play the most important role for musculoskeletal pain relief. The objective of this review is to investigate the role of the DIPM in musculoskeletal pain following HVLAM as well as to identify the pain-relieving importance of this technique within clinical practice. English literature databases were searched to find studies related to the objective of the present review. Findings from current literature support that HVLAM has a profound influence on nociceptive stimulus via the possible activation of the DIPM. It seems that the application of this technique activates the periaqueductal gray region area of the midbrain, stimulates the noradrenergic descending system and at the level of the spinal cord, the nociceptive afferent barrage is reduced and mechanical hypoalgesia is induced. However, the literature on HVLAM induced-analgesia is still problematic regarding the methodological design of the existing research. Despite these limitations, the clinical importance of the activation of the DIPM should not be ignored since the resulted analgesic effect of this technique can provide a window of opportunity to restore impaired physical performance and disability.

Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons.

Exercise (physical activity) has been proposed as a treatment for drug addiction. In rodents, voluntary wheel running reduces cocaine and nicotine seeking during extinction, and reinstatement of cocaine seeking triggered by drug-cues. The purpose of this study was to examine the effects of chronic wheel running during withdrawal and protracted abstinence on extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats, and to determine a potential neurobiological correlate underlying the effects. Rats were given extended access to methamphetamine (0.05mg/kg, 6h/day) for 22 sessions. Rats were withdrawn and were given access to running wheels (wheel runners) or no wheels (sedentary) for 3weeks after which they experienced extinction and reinstatement of methamphetamine seeking. Extended access to methamphetamine self-administration produced escalation in methamphetamine intake. Methamphetamine experience reduced running output, and conversely, access to wheel running during withdrawal reduced responding during extinction and, context- and cue-induced reinstatement of methamphetamine seeking. Immunohistochemical analysis of brain tissue demonstrated that wheel running during withdrawal did not regulate markers of methamphetamine neurotoxicity (neurogenesis, neuronal nitric oxide synthase, vesicular monoamine transporter-2) and cellular activation (c-Fos) in brain regions involved in relapse to drug seeking. However, reduced methamphetamine seeking was associated with running-induced reduction (and normalization) of the number of tyrosine hydroxylase immunoreactive neurons in the periaqueductal gray (PAG). The present study provides evidence that dopamine neurons of the PAG region show adaptive biochemical changes during methamphetamine seeking in methamphetamine dependent rats and wheel running abolishes these effects. Given that the PAG dopamine neurons project onto the structures of the extended amygdala, the present findings also suggest that wheel running may be preventing certain allostatic changes in the brain reward and stress systems contributing to the negative reinforcement and perpetuation of the addiction cycle.