Depth relationships and measures of tissue thickness in dorsal midbrain.

Dorsal human midbrain contains two nuclei with clear laminar organization, the superior and inferior colliculi. These nuclei extend in depth between the superficial dorsal surface of midbrain and a deep midbrain nucleus, the periaqueductal gray matter (PAG). The PAG, in turn, surrounds the cerebral aqueduct (CA). This study examined the use of two depth metrics to characterize depth and thickness relationships within dorsal midbrain using the superficial surface of midbrain and CA as references. The first utilized nearest-neighbor Euclidean distance from one reference surface, while the second used a level-set approach that combines signed distances from both reference surfaces. Both depth methods provided similar functional depth profiles generated by saccadic eye movements in a functional MRI task, confirming their efficacy for delineating depth for superficial functional activity. Next, the boundaries of the PAG were estimated using Euclidean distance together with elliptical fitting, indicating that the PAG can be readily characterized by a smooth surface surrounding PAG. Finally, we used the level-set approach to measure tissue depth between the superficial surface and the PAG, thus characterizing the variable thickness of the colliculi. Overall, this study demonstrates depth-mapping schemes for human midbrain that enables accurate segmentation of the PAG and consistent depth and thickness estimates of the superior and inferior colliculi.

Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks.

Human minds often wander away from their immediate sensory environment. It remains unknown whether such mind wandering is unsystematic or whether it lawfully relates to an individual's tendency to attend to salient stimuli such as pain and their associated brain structure/function. Studies of pain-cognition interactions typically examine explicit manipulation of attention rather than spontaneous mind wandering. Here we sought to better represent natural fluctuations in pain in daily life, so we assessed behavioral and neural aspects of spontaneous disengagement of attention from pain. We found that an individual's tendency to attend to pain related to the disruptive effect of pain on his or her cognitive task performance. Next, we linked behavioral findings to neural networks with strikingly convergent evidence from functional magnetic resonance imaging during pain coupled with thought probes of mind wandering, dynamic resting state activity fluctuations, and diffusion MRI. We found that (i) pain-induced default mode network (DMN) deactivations were attenuated during mind wandering away from pain; (ii) functional connectivity fluctuations between the DMN and periaqueductal gray (PAG) dynamically tracked spontaneous attention away from pain; and (iii) across individuals, stronger PAG-DMN structural connectivity and more dynamic resting state PAG-DMN functional connectivity were associated with the tendency to mind wander away from pain. These data demonstrate that individual tendencies to mind wander away from pain, in the absence of explicit manipulation, are subserved by functional and structural connectivity within and between default mode and antinociceptive descending modulation networks.

Functional subdivision of the human periaqueductal grey in respiratory control using 7 tesla fMRI.

The periaqueductal grey (PAG) is a nucleus within the midbrain, and evidence from animal models has identified its role in many homeostatic systems including respiration. Animal models have also demonstrated a columnar structure that subdivides the PAG into four columns on each side, and these subdivisions have different functions with regard to respiration. In this study we used ultra-high field functional MRI (7 T) to image the brainstem and superior cortical areas at high resolution (1mm(3)voxels), aiming to identify activation within the columns of the PAG associated with respiratory control. Our results showed deactivation in the lateral and dorsomedial columns of the PAG corresponding with short (~10s) breath holds, along with cortical activations consistent with previous respiratory imaging studies. These results demonstrate the involvement of the lateral and dorsomedial PAG in the network of conscious respiratory control for the first time in humans. This study also reveals the opportunities of 7 T functional MRI for non-invasively investigating human brainstem nuclei at high-resolutions.

Connectivity-based segmentation of the periaqueductal gray matter in human with brainstem optimized diffusion MRI.

The periaqueductal gray matter (PAG) is a midbrain structure, involved in key homeostatic neurobiological functions, such as pain modulation and cardiorespiratory control. Animal research has identified four subdivisional columns that differ in both connectivity and function. Until now these findings have not been replicated in humans. This study used high-resolution brainstem optimized diffusion magnetic resonance imaging and probabilistic tractography to segment the human PAG into four subdivisions, based on voxel connectivity profiles. We identified four distinct subdivisions demonstrating high spatial concordance with the columns of the animal model. The resolution of these subdivisions for individual subjects permitted detailed examination of their structural connectivity without the requirement of an a priori starting location. Interestingly patterns of forebrain connectivity appear to be different to those found in nonhuman studies, whereas midbrain and hindbrain connectivity appears to be maintained. Although there are similarities in the columnar structure of the PAG subdivisions between humans and nonhuman animals, there appears to be different patterns of cortical connectivity. This suggests that the functional organization of the PAG may be different between species, and as a consequence, functional studies in nonhumans may not be directly translatable to humans. This highlights the need for focused functional studies in humans.

Periaqueductal gray matter modulates the hypercapnic ventilatory response.

The periaqueductal gray (PAG) is a midbrain structure directly involved in the modulation of defensive behaviors. It has direct projections to several central nuclei that are involved in cardiorespiratory control. Although PAG stimulation is known to elicit respiratory responses, the role of the PAG in the CO(2)-drive to breathe is still unknown. The present study assessed the effect of chemical lesion of the dorsolateral and dorsomedial and ventrolateral/lateral PAG (dlPAG, dmPAG, and vPAG, respectively) on cardiorespiratory and thermal responses to hypercapnia. Ibotenic acid (IBO) or vehicle (PBS, Sham group) was injected into the dlPAG, dmPAG, or vPAG of male Wistar rats. Rats with lesions outside the dlPAG, dmPAG, or vPAG were considered as negative controls (NC). Pulmonary ventilation (VE: ), mean arterial pressure (MAP), heart rate (HR), and body temperature (Tb) were measured in unanesthetized rats during normocapnia and hypercapnic exposure (5, 15, 30 min, 7 % CO(2)). IBO lesioning of the dlPAG/dmPAG caused 31 % and 26.5 % reductions of the respiratory response to CO(2) (1,094.3 ± 115 mL/kg/min) compared with Sham (1,589.5 ± 88.1 mL/kg/min) and NC groups (1,488.2 ± 47.7 mL/kg/min), respectively. IBO lesioning of the vPAG caused 26.6 % and 21 % reductions of CO(2) hyperpnea (1,215.3 ± 108.6 mL/kg/min) compared with Sham (1,657.3 ± 173.9 mL/kg/min) and NC groups (1,537.6 ± 59.3). Basal VE: , MAP, HR, and Tb were not affected by dlPAG, dmPAG, or vPAG lesioning. The results suggest that dlPAG, dmPAG, and vPAG modulate hypercapnic ventilatory responses in rats but do not affect MAP, HR, or Tb regulation in resting conditions or during hypercapnia.

Interactions between chemokine and mu-opioid receptors: anatomical findings and electrophysiological studies in the rat periaqueductal grey.

Opioids have immunomodulatory functions and may alter susceptibility to immune disorders. Behavioral studies also indicate that chemokines, molecules expressed by immune cells, block opioid-induced analgesia in the periaqueductal grey (PAG). Bi-directional heterologous desensitization of opioid and chemokine receptors has been described in cell systems. We report the anatomical and functional interactions of chemokine receptors with the mu-opioid receptor (MOR) in the rat brain. The chemokine receptors, CXCR4 and CX3CR1, as well as their chemokine substrates, CXCL12 and CX3CL1, are widely expressed in the central nervous system (CNS). Immunohistochemical techniques were utilized to investigate MOR-CXCR4 and MOR-CX3CR1 receptor colocalization in multiple brain areas. Our results demonstrate co-expression of these receptors on individual neurons in several regions including cingulate cortex, hippocampus, and PAG, suggesting functional receptor interactions. Whole-cell patch-clamp recordings of PAG neurons in a rat brain slice preparation were used to examine morphine or chemokine (CXCL12, CX3CL1) effects alone, or in combination on neuronal membrane properties. Morphine (10 µM) hyperpolarized and reduced input resistance of PAG neurons. CXCL12 and CX3CL1 (10 nM) had no impact on either parameter. In the presence of CXCL12, morphine's electrophysiological effects were blocked in all neurons examined, whereas with CX3CL1, morphine's effects were blocked in 57% of neurons studied. The data provide electrophysiological evidence for MOR-CXCR4 and MOR-CX3CR1 heterologous desensitization in the PAG at the single-cell level. These interactions may contribute to the limited utility of opioid analgesics for inflammatory pain treatment and supports chemokines as neuromodulators.

Nocistatin and nociceptin exert opposite effects on the excitability of central amygdala nucleus-periaqueductal gray projection neurons.

Central amygdala nucleus (CeA)-periaqueductal gray (PAG) pathway is the component of descending antinociceptive circuitry. Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) produce supraspinal pronociceptive and antinociceptive effects, respectively. We hypothesized that opposite effects of N/OFQ and NST on supraspinal pain modulation result from their opposing effects on the excitability of CeA-PAG projection neurons. This hypothesis was tested by investigating electrophysiological effects of N/OFQ and NST on medial CeA neurons that project to PAG (CeA(M)-PAG). N/OFQ hyperpolarized CeA(M)-PAG projection neurons by enhancing inwardly rectifying potassium conductance. In contrast, NST depolarized CeA(M)-PAG neurons by causing the opening of TRPC cation channels via G(alphaq/11)-PLC-PKC pathway. CeA(M)-PAG neurons hyperpolarized by N/OFQ express CRF or neurotensin mRNA. NST-responsive CeA(M)-PAG neurons contain CRF or substance P mRNA. Our study provides the evidence that the molecular and cellular basis for opposite effects of N/OFQ and NST on supraspinal pain regulation is their opposing effects on the excitability of peptidergic CeA(M)-PAG neurons.

Grey and white matter proportional relationships in the cerebellar vermis altered in schizophrenia.

Magnetic resonance imaging studies frequently report abnormalities of the cerebellar vermis in schizophrenia, though with some discrepancies as to the nature and location of such abnormalities. Imaging studies typically investigate volumetric differences between groups. Yet substantial evidence supports the hypothesis that grey and white matter proportions in the mammalian brain are controlled by scaling relationships. If strong proportional relationships between grey and white matter tissue volumes are observed in the healthy vermis, then disturbances to these proportions might characterize vermian dysmorphology in schizophrenia. Measures of grey and white matter tissue volumes from three anatomical divisions of the vermis were obtained from 52 patients with chronic schizophrenia and 55 healthy controls. Cross-correlations of the tissue class volumes were computed for each subject group, controlling for age. The number of significant correlations in each group were compared. In addition, the grey/white matter ratio was computed within and across each vermian division. Differences in mean and variance were assessed using t and F tests. A false discovery rate of 0.05 controlled for multiple comparisons. Among controls, 11 of 15 correlations were significant. Among patients, eight of 15 correlations were significant. Five of the nine grey/white matter ratios had an increased mean in the patient group, and all of the variances were trend level or significantly increased in the patients. Tissue class volumes in the cerebellar vermis were strongly interrelated in controls. These relationships were disturbed in patients with schizophrenia.

Gray matter deficits in young adults with narcolepsy.

OBJECTIVES: The aim of this study was to investigate gray matter volume changes in narcolepsy. MATERIALS AND METHODS: An optimized voxel-based morphometry was conducted for 17 young adults with a sole diagnosis of human leukocyte antigen DQB(1) 0602 positive narcolepsy with cataplexy (26.6 +/- 5.2 years old) and 17 comparison subjects (24.6 +/- 4.9 years old) using 3 Tesla scanner. Gray matter volumes in the bilateral hypothalamic voxel of interests (VOI) were also calculated. RESULTS: Compared with the comparison subjects, narcoleptic patients had gray matter volume decrease in the right hypothalamus and other regions including subcortical, prefrontal, limbic and occipital areas. Narcoleptic patients also had lower gray matter volume on predefined VOI at the bilateral hypothalamus, which correlated with the Ullanlinna Narcolepsy Scale score. CONCLUSIONS: Current findings suggest that narcoleptic patients have structural abnormalities in hypothalamus, which might be related to the clinical manifestation of narcolepsy with cataplexy.

Afferent connections to the rostrolateral part of the periaqueductal gray: a critical region influencing the motivation drive to hunt and forage.

Previous studies have shown that a particular site in the periaqueductal gray (PAG), the rostrolateral PAG, influences the motivation drive to forage or hunt. To have a deeper understanding on the putative paths involved in the decision-making process between foraging, hunting, and other behavioral responses, in the present investigation, we carried out a systematic analysis of the neural inputs to the rostrolateral PAG (rlPAG), using Fluorogold as a retrograde tracer. According to the present findings, the rlPAG appears to be importantly driven by medial prefrontal cortical areas involved in controlling attention-related and decision-making processes. Moreover, the rlPAG also receives a wealth of information from different amygdalar, hypothalamic, and brainstem sites related to feeding, drinking, or hunting behavioral responses. Therefore, this unique combination of afferent connections puts the rlPAG in a privileged position to influence the motivation drive to choose whether hunting and foraging would be the most appropriate adaptive responses.

Viral vector induction of CREB expression in the periaqueductal gray induces a predator stress-like pattern of changes in pCREB expression, neuroplasticity, and anxiety in rodents.

Predator stress is lastingly anxiogenic. Phosphorylation of CREB to pCREB (phosphorylated cyclic AMP response element binding protein) is increased after predator stress in fear circuitry, including in the right lateral column of the PAG (periaqueductal gray). Predator stress also potentiates right but not left CeA-PAG (central amygdala-PAG) transmission up to 12 days after stress. The present study explored the functional significance of pCREB changes by increasing CREB expression in non-predator stressed rats through viral vectoring, and assessing the behavioral, electrophysiological and pCREB expression changes in comparison with handled and predator stressed controls. Increasing CREB expression in right PAG was anxiogenic in the elevated plus maze, had no effect on risk assessment, and increased acoustic startle response while delaying startle habituation. Potentiation of the right but not left CeA-PAG pathway was also observed. pCREB expression was slightly elevated in the right lateral column of the PAG, while the dorsal and ventral columns were not affected. The findings of this study suggest that by increasing CREB and pCREB in the right lateral PAG, it is possible to produce rats that exhibit behavioral, brain, and molecular changes that closely resemble those seen in predator stressed rats.

Are periaqueductal gray and dorsal raphe the foundation of appetitive and aversive control? A comprehensive review.

Many see the periaqueductal gray (PAG) as a region responsible for the downstream control of defensive reactions. Here we provide a detailed review of anatomical and functional data on the different parts of the PAG together with the dorsal raphe, which completes the circle of periaqueductal nuclei. Based on anatomical features, we propose a new subdivision of the periaqueductal gray that accounts for the distinct characteristics of the area. We provide a comprehensive functional view of the periaqueductal gray, going beyond simple panic and escape to integrate data on fear, anxiety, and depression. Importantly, we conclude that this periaqueductal cluster of nuclei is broadly involved in motivated behavior controlling not only aversive but also appetitive behavior and with some involvement in more complex motivational processes such as approach-avoidance conflict resolution. In sum, these highly conserved nuclei surrounding the aqueduct appear to be the simplest, foundational, elements of integrated motivated goal-directed control of all types.

Hypothalamic sites responding to predator threats--the role of the dorsal premammillary nucleus in unconditioned and conditioned antipredatory defensive behavior.

In this study we provide a comprehensive analysis of the hypothalamic activation pattern during exposure to a live predator or an environment previously associated with a predator. Our results support the view that hypothalamic processing of the actual and the contextual predatory threats share the same circuit, in which the dorsal premammillary nucleus (PMd) plays a pivotal role in amplifying this processing. To further understand the role of the PMd in the circuit organizing antipredatory defensive behaviors, we studied rats with cytotoxic PMd lesions during cat exposure and examined the pattern of behavioral responses as well as how PMd lesions affect the neuronal activation of the systems engaged in predator detection, in contextual memory formation and in defensive behavioral responses. Next, we investigated how pharmacological blockade of the PMd interferes with the conditioned behavioral responses to a context previously associated with a predator, and how this blockade affects the activation pattern of periaqueductal gray (PAG) sites likely to organize the conditioned behavioral responses to the predatory context. Behavioral observations indicate that the PMd interferes with both unconditioned and conditioned antipredatory defensive behavior. Moreover, we have shown that the PMd influences the activation of its major projecting targets, i.e. the ventral part of the anteromedial thalamic nucleus which is likely to influence mnemonic processing, and PAG sites involved in the expression of antipredatory unconditioned and conditioned behavioral responses. Of particular relevance, this work provides evidence to elucidate the basic organization of the neural circuits integrating unconditioned and contextual conditioned responses to predatory threats.

Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats.

RATIONALE: Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa plant that induces anxiolytic effects. However, the brain sites and mechanisms of these effects remain poorly understood. The dorsolateral periaqueductal gray (dlPAG) is a midbrain structure related to anxiety that contains receptors proposed to interact with CBD such as 5HT1A. In addition, since CBD has been shown to inhibit anandamide metabolism, CB1 receptors could also be involved in the effects of this cannabinoid. OBJECTIVES: To investigate if the dlPAG could be a possible site of the anxiolytic effects induced by CBD and if these effects depend on CB1 or 5HT1A receptors. MATERIALS AND METHODS: Male Wistar rats with cannulae aimed at the dlPAG were tested in the elevated plus maze (EPM) and the Vogel conflict test (VCT). RESULTS: CBD injected into the dlPAG produced anxiolytic-like effects in the EPM with a bell-shaped dose-response curve. The anxiolytic effect of CBD was confirmed in the VCT. These effects were prevented by WAY100635, a 5HT1A receptor antagonist, but not by AM251, an antagonist of CB1 receptors. CONCLUSION: These results suggest the CBD interacts with 5HT1A receptors to produce anxiolytic effects in the dlPAG.

Alprazolam potentiates the antiaversive effect induced by the activation of 5-HT(1A) and 5-HT (2A) receptors in the rat dorsal periaqueductal gray.

RATIONALE: Serotonin in the dorsal periaqueductal gray (DPAG) through the activation of 5-HT(1A) and 5-HT(2A) receptors inhibits escape, a defensive behavior associated with panic attacks. Long-term treatment with antipanic drugs that nonselectively or selectively blocks the reuptake of serotonin (e.g., imipramine and fluoxetine, respectively) enhances the inhibitory effect on escape caused by intra-DPAG injection of 5-HT(1A) and 5-HT(2A) receptor agonists. It has been proposed that these compounds exert their effect on panic by facilitating 5-HT-mediated neurotransmission in the DPAG. OBJECTIVES: The objective of this study was to investigate whether facilitation of 5-HT neurotransmission in the DPAG is also observed after treatment with alprazolam, a pharmacologically distinct antipanic drug that acts primarily as a high potency benzodiazepine receptor agonist. MATERIALS AND METHODS: Male Wistar rats, subchronically (3-6 days) or chronically (14-17 days) treated with alprazolam (2 and 4 mg/kg, i.p.) were intra-DPAG injected with (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), (+/-)-1-(2,5-dimethoxy-4-iodophenyl) piperazine dihydrochloride (DOI), and midazolam, respectively, 5-HT(1A), 5-HT(2A/2C), and benzodiazepine receptor agonists. The intensity of electrical current that needed to be applied to the DPAG to evoke escape behavior was measured before and after the microinjection of these agonists. RESULTS: Intra-DPAG injection of the 5-HT agonists and midazolam increased the escape threshold in all groups of animals tested, indicating a panicolytic-like effect. The inhibitory effect of 8-OH-DPAT and DOI, but not midazolam, was significantly higher in animals receiving long-, but not short-term treatment with alprazolam. CONCLUSIONS: Alprazolam as antidepressants compounds facilitates 5-HT(1A)- and 5-HT(2A)-receptor-mediated neurotransmission in the DPAG, implicating this effect in the mode of action of different classes of antipanic drugs.

Activation of CB1 cannabinoid receptors in the dorsolateral periaqueductal gray reduces the expression of contextual fear conditioning in rats.

RATIONALE: Conditioned fear to context causes freezing and cardiovascular changes in rodents and has been used to measure anxiety. It also activates the dorsolateral column of the periaqueductal gray (dlPAG). Microinjections of cannabinoid agonists into the dlPAG produced anxiolytic-like effects in the elevated plus maze, but the effects of these treatments on fear conditioning remains unknown. OBJECTIVE: The objective of this study was to verify if intra-dlPAG injection of the CB1 cannabinoid receptor agonist anandamide (AEA) or the anandamide transport inhibitor AM404 would attenuate behavioral (freezing) and cardiovascular (increase of arterial pressure and heart rate) responses of rats submitted to a contextual fear-conditioning paradigm. MATERIALS AND METHODS: Male Wistar rats with cannulae aimed at the dlPAG were re-exposed to a chamber where they had received footshocks 48 h before. Fifteen minutes before the test, the animals received a first intra-dlPAG injection of vehicle or AM251, a CB1 receptor antagonist (100 pmol/200 nl), followed 5 min later by vehicle, AEA (5 pmol/200 nl) or AM404 (50 pmol/200 nl). Freezing and cardiovascular responses were recorded for 10 min. RESULTS: Freezing and cardiovascular responses were reduced by administration of either AEA or AM404 into the dlPAG before re-exposition to the aversively conditioned context. These effects were abolished when the animals were locally pretreated with AM251. The latter drug, even at a higher dose (300 pmol), was ineffective when administered alone into the dlPAG. CONCLUSION: The results suggest that facilitation of endocannabinoid-mediated neurotransmission in the dlPAG, through activation of local CB1 receptors, attenuates the expression of contextual fear responses.

Microinjection of the vehicle dimethyl sulfoxide (DMSO) into the periaqueductal gray modulates morphine antinociception.

Dimethyl sulfoxide (DMSO) is commonly used as a solvent for water-insoluble drugs. Given that DMSO has varying cellular and behavioral effects ranging from increased membrane permeability to toxicity, microinjection of DMSO as a vehicle could confound the effects of other drugs. For example, DMSO is often used as a vehicle for studies examining the neurochemical mechanisms underlying morphine antinociception. Given that the ventrolateral periaqueductal gray (vlPAG) plays a major role in morphine antinociception and tolerance, the effects of DMSO on morphine antinociception mediated by the vlPAG needs to be evaluated. The present experiment tested whether co-administration of DMSO (0, 0.2, 2, or 20%) would alter the antinociceptive effect of microinjecting morphine into the vlPAG. DMSO had no effect on nociception when microinjected into the vlPAG alone, but 2% DMSO enhanced morphine potency when co-administered with morphine. In contrast, twice daily microinjections of DMSO (5 or 20%) for two days reduced the potency of subsequent microinjections of morphine into the vlPAG--an effect that persisted for at least one week. A similar rightward shift in the morphine dose-response curve was caused by morphine tolerance. Co-administration of morphine and DMSO during the pretreatment did not cause a greater shift in the morphine dose-response curve compared to morphine pretreated alone. In conclusion, DMSO can alter morphine antinociception following both acute (enhancement) and chronic (inhibition) administration depending on the concentration. These data reinforce the need to be cautious when using DMSO as a vehicle for drug administration.

Regulation of conditioned and unconditioned fear in rats by 5-HT1A receptors in the dorsal periaqueductal gray.

Studies on the involvement of 5-HT1-mediated mechanisms in the dorsal periaqueductal gray (dPAG) of animals with past stressful experiences have not been conducted so far. We investigated the role of 5-HT1 receptors in the dPAG of rats previously submitted to contextual fear conditioning. Defensive behaviors induced by activation of the dPAG were assessed by measuring the lowest electric current applied to this structure (threshold) able to produce freezing and escape responses during testing sessions of contextual fear conditioning, in which animals were placed in a context previously paired to footshocks. The 5-HT1A function of the dPAG was evaluated by local injections of 8-OH-DPAT (4 and 8 nmol/0.2 microL) and WAY-100635 (10 nmol/0.2 microL), selective agonist and antagonist of 5-HT1A receptors, respectively. In accordance with previous studies, 8-OH-DPAT increased aversive thresholds (antiaversive effects) but injections of WAY 100635 into the dPAG did not produce significant effects on the aversive thresholds in naive rats. However, the aversive thresholds of animals exhibiting contextual fear remained unchanged with both treatments. Moreover, 8-OH-DPAT and WAY 100635 did not change the dPAG post-stimulation freezing. The present results suggest that the stressful experience of being fear conditioned has an effect on the role of the 5-HT1A receptors in mediating unconditioned fear. Also, the reduction in the regulation of the defensive behaviors by 5-HT1A-mediated mechanisms in the dPAG of these animals may underlie the stress precipitated psychopathology associated with the neural substrates of aversion of the dPAG.

Regional grey matter volumetric changes in forensic schizophrenia patients: an MRI study comparing the brain structure of patients who have seriously and violently offended with that of patients who have not.

BACKGROUND: The aim was to carry out the first voxel-based morphometry study of grey matter changes in the whole brain in schizophrenia associated with a history of seriously and violently offending. METHODS: Structural cerebral magnetic resonance imaging scans of 26 patients with schizophrenia were analyzed using voxel-based morphometry: 13 of the patients had seriously and violently offended directly as a result of schizophrenia prior to admission, the offences consisting of homicide, attempted murder or wounding with intent to cause grievous bodily harm; the other 13 patients did not have a history of violence. There was no history of comorbid psychoactive substance misuse disorder in any of the patients. Voxelwise generalized linear modelling was applied to the processed magnetic resonance data using permutation-based non-parametric testing, forming clusters at t > 2.3 and testing clusters for significance at p < 0.05, corrected for multiple comparisons across space. RESULTS: The two groups of patients were matched with respect to age, gender and duration of illness, but the group with a history of serious violence was on average receiving a higher dose of antipsychotic medication than the group without a history of violence. There were local regions of reduced grey matter volume in the schizophrenia patient group with a history of serious and violent offending, compared with the schizophrenia patient group without such a history. Significant voxels (p < 0.05, corrected for multiple comparisons) were noted bilaterally in the cerebellum and in BA 39 and 40. CONCLUSION: These regions are important in verbal working memory. The cerebellum may integrate inputs from ventrolateral prefrontal cortex and parietal regions, providing a corrective signal that refines the process of rehearing the contents of the phonological store. A strong connection has been hypothesized between the supramarginal region corresponding to BA 39/40 and Broca's area, which may correspond largely to the arcuate fasciculus, with the connectional pattern of the language regions of this model fitting the network of parietotemporal-prefrontal connections that participate in working memory. Therefore our results point to the possibility of an abnormality in neural circuits involved in verbal working memory in this group of patients.

Pre-operative DTI and probabilisitic tractography in four patients with deep brain stimulation for chronic pain.

This study aimed to examine, using diffusion tensor imaging (DTI), differences in electrode placement in four patients undergoing deep brain stimulation for chronic neuropathic pain of varying aetiology. A pre-operative DTI was obtained for each patient, who was then implanted with deep brain stimulation electrodes in the periventricular/periaqueductal grey area with good pain relief. Using seeds from the postoperative MRI scan, probabilistic tractography was performed from the pre-operative DTI.