A Voxel-Based Morphometry Study of Frontal Gray Matter Correlates of Impulsivity

Impulsivity is a personality trait exhibited by healthy individuals, but excessive impulsivity is associated with some mental disorders. Lesion and functional, neuroimaging Studies indicate that the ventromedial prefrontal region (VMPFC), including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC) and medial prefrontal cortex, and the amygdala may modulate impulsivity and aggression. However, no morphometric study has examined the association between VMPFC and impulsivity. We hypothesized that healthy subjects with high impulsivity would have smaller volumes in these brain regions compared with those with low impulsivity. Sixty-two healthy Subjects were Studied (age 35.4 +/- 12.1 years) using a 1.5-T MRI system. The Barratt impulsiveness scale (BIS) was used to assess impulsivity. Images were processed using an optimized voxel-based morphometry (VBM) protocol. We calculated the correlations between BIS scale scores and the gray matter (GM) and white matter (WM) volumes of VMPFC and amygdala. GM volumes of the left and right OFC were inversely correlated with the BIS total score (P = 0.04 and 0.02, respectively). Left ACC GM Volumes had a tendency to be inversely correlated with the BIS total score (P = 0.05. Right OFC GM Volumes were inversely correlated with BIS nonplanning impulsivity, and left OFC GM volumes were inversely correlated with motor impulsivity. There were no significant WM volume correlations with impulsivity. The results Of this morphometry Study indicate that small OFC volume relate to high impulsivity and extend the prior finding that the VMPFC is involved in the circuit modulating impulsivity. HUM Brain Mapp 30:1188-1195, 2009. (C) 2008 Wiley-Liss, Inc.

Gray Matter Volumes in Obsessive-Compulsive Disorder Before and After Fluoxetine or Cognitive-Behavior Therapy: A Randomized Clinical Trial

Serotonin reuptake inhibitors and cognitive-behavior therapy (CBT) are considered first-line treatments for obsessive-compulsive disorder (OCD). However, little is known about their modulatory effects on regional brain morphology in OCD patients. We sought to document structural brain abnormalities in treatment-naive OCD patients and to determine the effects of pharmacological and cognitive-behavioral treatments on regional brain volumes. Treatment-naive patients with OCD (n = 38) underwent structural magnetic resonance imaging scan before and after a 12-week randomized clinical trial with either fluoxetine or group CBT. Matched-healthy controls (n = 36) were also scanned at baseline. Voxel-based morphometry was used to compare regional gray matter (GM) volumes of regions of interest (ROIs) placed in the orbitofrontal, anterior cingulate and temporolimbic cortices, striatum, and thalamus. Treatment-naive OCD patients presented smaller GM volume in the left putamen, bilateral medial orbitofrontal, and left anterior cingulate cortices than did controls (p<0.05, corrected for multiple comparisons). After treatment with either fluoxetine or CBT (n = 26), GM volume abnormalities in the left putamen were no longer detectable relative to controls. ROI-based within-group comparisons revealed that GM volume in the left putamen significantly increased (p<0.012) in fluoxetine-treated patients (n = 13), whereas no significant GM volume changes were observed in CBT-treated patients (n = 13). This study supports the involvement of orbitofronto/cingulo-striatal loops in the pathophysiology of OCD and suggests that fluoxetine and CBT may have distinct neurobiological mechanisms of action. Neuropsychopharmacology (2012) 37, 734-745; doi: 10.1038/npp.2011.250; published online 26 October 2011

Deep gray matter atrophy in multiple sclerosis: a tensor based morphometry.

Tensor based morphometry (TBM) was applied to determine the atrophy of deep gray matter (DGM) structures in 88 relapsing multiple sclerosis (MS) patients. For group analysis of atrophy, an unbiased atlas was constructed from 20 normal brains. The MS brain images were co-registered with the unbiased atlas using a symmetric inverse consistent nonlinear registration. These studies demonstrate significant atrophy of thalamus, caudate nucleus, and putamen even at a modest clinical disability, as assessed by the expanded disability status score (EDSS). A significant correlation between atrophy and EDSS was observed for different DGM structures: (thalamus: r=-0.51, p=3.85 x 10(-7); caudate nucleus: r=-0.43, p=2.35 x 10(-5); putamen: r=-0.36, p=6.12 x 10(-6)). Atrophy of these structures also correlated with 1) T2 hyperintense lesion volumes (thalamus: r=-0.56, p=9.96 x 10(-9); caudate nucleus: r=-0.31, p=3.10 x 10(-3); putamen: r=-0.50, p=6.06 x 10(-7)), 2) T1 hypointense lesion volumes (thalamus: r=-0.61, p=2.29 x 10(-10); caudate nucleus: r=-0.35, p=9.51 x 10(-4); putamen: r=-0.43, p=3.51 x 10(-5)), and 3) normalized CSF volume (thalamus: r=-0.66, p=3.55 x 10(-12); caudate nucleus: r=-0.52, p=2.31 x 10(-7), and putamen: r=-0.66, r=2.13 x 10(-12)). More severe atrophy was observed mainly in thalamus at higher EDSS. These studies appear to suggest a link between the white matter damage and DGM atrophy in MS.

A universal scaling law between gray matter and white matter of cerebral cortex

Neocortex, a new and rapidly evolving brain structure in mammals, has a similar layered architecture in species over a wide range of brain sizes. Larger brains require longer fibers to communicate between distant cortical areas; the volume of the white matter that contains long axons increases disproportionally faster than the volume of the gray matter that contains cell bodies, dendrites, and axons for local information processing, according to a power law. The theoretical analysis presented here shows how this remarkable anatomical regularity might arise naturally as a consequence of the local uniformity of the cortex and the requirement for compact arrangement of long axonal fibers. The predicted power law with an exponent of 4/3 minus a small correction for the thickness of the cortex accurately accounts for empirical data spanning several orders of magnitude in brain sizes for various mammalian species, including human and nonhuman primates.

The impact of general intellectual ability and white matter volume on the functional outcome of patients with bipolar disorder and their relatives

Background: There is substantial evidence that cognitive deficits and brain structural abnormalities are present in patients with Bipolar Disorder (BD) and in their first-degree relatives. Previous studies have demonstrated associations between cognition and functional outcome in BD patients but have not examined the role of brain morphological changes. Similarly, the functional impact of either cognition or brain morphology in relatives remains unknown. Therefore we focused on delineating the relationship between psychosocial functioning, cognition and brain structure, in relation to disease expression and genetic risk for BD. Methods: Clinical, cognitive and brain structural measures were obtained from 41 euthymic BD patients and 50 of their unaffected first-degree relatives. Psychosocial function was evaluated using the General Assessment of Functioning (GAF) scale. We examined the relationship between level of functioning and general intellectual ability (IQ), memory, attention, executive functioning, symptomatology, illness course and total gray matter, white matter and cerebrospinal fluid volumes. Limitations: Cross-sectional design. Results: Multiple regression analyses revealed that IQ, total white matter volume and a predominantly depressive illness course were independently associated with functional outcome in BD patients, but not in their relatives, and accounted for a substantial proportion (53%) of the variance in patients' GAF scores. There were no significant domain-specific associations between cognition and outcome after consideration of IQ. Conclusions: Our results emphasise the role of IQ and white matter integrity in relation to outcome in BD and carry significant implications for treatment interventions. © 2010 Elsevier B.V.

Striatal volume abnormalities in treatment-naive patients diagnosed with pediatric major depressive disorder

Objective: The striatum, including the putamen and caudate, plays an important role in executive and emotional processing and may be involved in the pathophysiology of mood disorders. Few studies have examined structural abnormalities of the striatum in pediatric major depressive disorder (MDD) patients. We report striatal volume abnormalities in medication-naive pediatric MDD compared to healthy comparison subjects. Method: Twenty seven medication-naive pediatric Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) MDD and 26 healthy comparison subjects underwent volumetric magnetic resonance imaging (MRI). The putamen and caudate volumes were traced manually by a blinded rater, and the patient and control groups were compared using analysis of covariance adjusting for age, sex, intelligence quotient, and total brain volumes. Results: MDD patients had significantly smaller right striatum (6.0% smaller) and right caudate volumes (7.4% smaller) compared to the healthy subjects. Left caudate volumes were inversely correlated with severity of depression in MDD subjects. Age was inversely correlated with left and right putamen volumes in MDD patients but not in the healthy subjects. Conclusions: These findings provide fresh evidence for abnormalities in the striatum of medication-naive pediatric MDD patients and suggest the possible involvement of the striatum in the pathophysiology of MDD.

Serotonin-1A receptors in the dorsal periaqueductal gray matter mediate the panicolytic-like effect of pindolol and paroxetine combination in the elevated T-maze

The beta-adrenergic blocker and 5-HT(1A) receptor antagonist pindolol has been combined with selective serotonin reuptake inhibitors (SSRIs) in patients with depressive and anxiety disorders to shorten the onset of the clinical action and/or increase the proportion of responders. The results of a previous study have shown that pindolol potentiates the panicolytic effect of paroxetine in rats submitted to the elevated T-maze (ETM). Since reported evidence has implicated the 5-HT(1A) receptors of the dorsal periaqueductal gray matter (DPAG) in the panicolytic effect of antidepressants, rats treated with pindolol (5.0 mg/kg, i.p.) and paroxetine (1.5 mg/kg, i.p.) received a previous intra-DPAG injection of the selective 5-HT(1A) antagonist, WAY-100635 (0.4 mu g) and were submitted to the ETM. Pretreatment with WAY-100635 reversed the increase in escape latency, a panicolytic effect, determined by the pindolol-paroxetine combination. These results implicate the 5-HT(1A) receptors of the DPAG in the panicolytic effect of the pindolol-paroxetine combination administered systemically. They also give further preclinical support for the use of this drug combination in the treatment of panic disorder. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Effect of temporal lobe structure volume on memory in elderly depressed patients

Objective: To compare the volume of the hippocampus and parahippocampal gyrus in elderly individuals with and without depressive disorders, and to determine whether the volumes of these regions correlate with scores on memory tests. Method: Clinical and demographic differences, as well as differences in regional gray matter volumes, were assessed in 48 elderly patients with depressive disorders and 31 control subjects. Brain (structural MRI) scans were processed using statistical parametric mapping and voxel-based morphometry. Cognitive tests were administered to subjects in both groups. Results: There were no between-group gray matter volume differences in the hippocampus or parahippocampal gyrus. In the elderly depressed group only, the volume of the left parahippocampal gyrus correlated with scores on the delayed naming portion of the visual verbal learning test. There were also significant direct correlations in depressed subjects between the volumes of the left hippocampus, right and left parahippocampal gyrus and immediate recall scores on verbal episodic memory tests and visual learning tests. In the control group, there were direct correlations only between overall cognitive performance (as assessed with the MMSE) and the volume of right hippocampus, and between the total score on the visual verbal learning test and the volume of the right and left parahippocampal gyrus. Conclusions: These findings highlight different patterns of relationship between cognitive performance and volumes of medial temporal structures in depressed individuals and healthy elderly subjects. The direct correlation between delayed visual verbal memory recall scores with left parahippocampal volumes specifically in elderly depressed individuals provides support to the view that depression in elderly populations may be a risk factor for dementia. (C) 2009 Elsevier Inc. All rights reserved.

Dorsal raphe nucleus regulation of a panic-like defensive behavior evoked by chemical stimulation of the rat dorsal periaqueductal gray matter

Electrical or chemical stimulation of the dorsal periaqueductal gray matter (DPAG) evokes escape, a defensive behavior that has been related to panic attacks. Injection of 5-HT(1A) or 5-HT(2A) receptor agonists into this midbrain area inhibits this response. It has been proposed that the impairment of 5-HT mechanisms controlling escape at the level of the DPAG may underlie the susceptibility to panic attacks that characterizes the panic disorder. In this study we evaluated the effects of the pharmacological manipulation of the dorsal raphe nucleus (DRN), which are the main source of 5-HT input to the DPAG, on the escape response evoked in rats by the intra-DPAG injection of the nitric oxide donor SIN-1. The results showed that DRN administration of the 5-HT(1A) receptor agonist 8-OH-DPAT which inhibits the activity of 5-HT neurons favored the expression of escape induced by SIN-1. Intra-DRN injection of the excitatory amino acid kainic acid or the 5-HT(1A) receptor antagonist WAY-100635 did not change escape expression. However, both compounds fully blocked the escape reaction generated by intra-DPAG injection of the excitatory amino acid D,L-homocysteic acid (DLH). Overall, the results indicate that 5-HT neurons in the DRN exert a bidirectional control upon escape behavior generated by the DPAG. Taking into account the effect of WAY-100635 on DLH-induced escape, they also strengthen the view that DRN 5-HT(1A) autoreceptors are under tonic inhibitory influence by 5-HT. (C) 2010 Elsevier B.V. All rights reserved.

The lateral habenula regulates defensive behaviors through changes in 5-HT-mediated neurotransmission in the dorsal periaqueductal gray matter

Chemical stimulation of the lateral nucleus of the habenula (LHb), an area implicated in the regulation of serotonergic activity in raphe nuclei, affects the acquisition of inhibitory avoidance and escape expression of rats submitted to the elevated T-maze test of anxiety. Here, we investigated whether facilitation of 5-HT-mediated neurotransmission in the dorsal periaqueductal gray (dPAG) accounts for the behavioral consequences in the elevated T-maze induced by chemical stimulation of the LHb. The dPAG in the midbrain, which is innervated by 5-HT fibers originating from the dorsal raphe nucleus (DRN), has been consistently implicated in the genesis/regulation of anxiety- and fear-related defensive responses. The results showed that intra-dPAG injection of WAY-100635 or ketanserin, 5-HT(1A) and 5-HT(2A/2C) receptor antagonists, respectively, counteracted the anti-escape effect caused by bilateral intra-LHb injection of kainic acid (60 pmol/0.2 mu l). Ketanserin, but not WAY-100635, blocked kainic acid`s facilitatory effect on inhibitory avoidance acquisition. Overall, the results suggest that the pathway connecting the LHb to the DRN is involved in the control of 5-HT release in the dPAG, and facilitation of 5-HT-mediated neurotransmission in the latter area distinctively impacts upon the expression of anxiety- and fear-related defensive behaviors. While stimulation of 5-HT(1A) receptors selectively affects escape performance, 5-HT(2A/2C) receptors modulate both inhibitory avoidance and escape. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

ANGIOTENSIN III MODULATES THE NOCICEPTIVE CONTROL MEDIATED BY THE PERIAQUEDUCTAL GRAY MATTER

Endogenous angiotensin (Ang) II and/or an Ang II-derived peptide, acting on Ang type I (AT(1)) and Ang type 2 (AT(2)) receptors, can carry out part of the nociceptive control modulated by periaqueductal gray matter (PAG). However, neither the identity of this putative Ang-peptide, nor its relationship to Ang II antinociceptive activity was clarified. Therefore, we have used tail-flick and incision allodynia models combined with an HPLC time course of Ang metabolism, to study the Ang III antinociceptive effect in the rat ventrolateral (vi) PAG using peptidase inhibitors and receptor antagonists. Ang III injection into the vIPAG increased tail-flick latency, which was fully blocked by Losartan and CGP 42,112A, but not by divalinal-Ang IV, indicating that. Ang III effect was mediated by AT(1) and AT(2) receptors, but not by the AT(4) receptor. Ang III injected into the vIPAG reduced incision allodynia. Incubation of Ang II with punches of vIPAG homogenate formed Ang III, Ang (1-7) and Ang IV. Amastatin (AM) inhibited the formation of Ang III from Ang II by homogenate, and blocked the antinociceptive activity of Ang II injection into vIPAG, suggesting that aminopeptidase A (APA) formed Ang III from Ang II. Ang III can also be formed from Ang I by a vIPAG alternative pathway. Therefore, the present work shows, for the first time, that: (i) Ang III, acting on AT(1) and AT(2) receptors, can elicit vIPAG-mediated antinociception, (ii) the conversion of Ang II to Ang III in the vIPAG is required to elicit antinociception, and (iii) the antinociceptive activity of endogenous Ang II in vIPAG can be ascribed preponderantly to Ang III. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.

Functional mapping of the periaqueductal gray matter involved in organizing tonic immobility behavior in guinea pigs

Tonic immobility behavior (TI) is an innate response characterized by profound motor inhibition that is exhibited by prey when physical contact with a predator is prolonged and the situation inescapable. The periaqueductal gray matter (PAG) is intimately associated with the somatic and autonomic components of defensive reactions. This study investigated whether the TI response was able to recruit specific functional columns of the PAG by examining c-fos immunolocalization in guinea pigs. In the TI group, the innate response was invoked in animals through inversion and physical contention for at least 15 min. In the control group, the animals were physically manipulated only. Our results demonstrate that the defensive behavior of TI is capable of promoting the expression of Fos protein in different areas of the PAG, with higher levels of staining in the ventrolateral (vI) and lateral (I) columns. In addition, our results demonstrate increased Fos immunoreactivity (FOS-IR) in the dorsal raphe nucleus, the Edinger-Westphal nucleus, the cuneiform nucleus and the superior colliculus. In contrast, there were no significant alterations in the number of FOS-IR cells in the inferior colliculus or the oculomotor nucleus. Analysis of the results suggests that neuronal activation after the TI response differs by functional column of the PAG. (C) 2010 Elsevier B.V. All rights reserved.

Dynamics of Gray Matter Loss in Alzheimer's Disease

We detected and mapped a dynamically spreading wave of gray matter loss in the brains of patients with Alzheimer's disease (AD). The loss pattern was visualized in four dimensions as it spread over time from temporal and limbic cortices into frontal and occipital brain regions, sparing sensorimotor cortices. The shifting deficits were asymmetric (left hemisphere >right hemisphere) and correlated with progressively declining cognitive status ( p 15% loss). The maps distinguished different phases of AD and differentiated AD from normal aging. Local gray matter loss rates (5.3 +/- 2.3% per year in AD v 0.9 +/- 0.9% per year in controls) were faster in the left hemisphere ( p < 0.029) than the right. Transient barriers to disease progression appeared at limbic/frontal boundaries. This degenerative sequence, observed in vivo as it developed, provides the first quantitative, dynamic visualization of cortical atrophic rates in normal elderly populations and in those with dementia.

Proton T1 relaxation times of metabolites in human occipital white and gray matter at 7 T.

Proton T1 relaxation times of metabolites in the human brain have not previously been published at 7 T. In this study, T1 values of CH3 and CH2 group of N-acetylaspartate and total creatine as well as nine other brain metabolites were measured in occipital white matter and gray matter at 7 T using an inversion-recovery technique combined with a newly implemented semi-adiabatic spin-echo full-intensity acquired localized spectroscopy sequence (echo time = 12 ms). The mean T1 values of metabolites in occipital white matter and gray matter ranged from 0.9 to 2.2 s. Among them, the T1 of glutathione, scyllo-inositol, taurine, phosphorylethanolamine, and N-acetylaspartylglutamate were determined for the first time in the human brain. Significant differences in T1 between white matter and gray matter were found for water (-28%), total choline (-14%), N-acetylaspartylglutamate (-29%), N-acetylaspartate (+4%), and glutamate (+8%). An increasing trend in T1 was observed when compared with previously reported values of N-acetylaspartate (CH3 ), total creatine (CH3 ), and total choline at 3 T. However, for N-acetylaspartate (CH3 ), total creatine, and total choline, no substantial differences compared to previously reported values at 9.4 T were discernible. The T1 values reported here will be useful for the quantification of metabolites and signal-to-noise optimization in human brain at 7 T. Magn Reson Med 69:931-936, 2013. © 2012 Wiley Periodicals, Inc.