RESEARCH

Dissociable executive processes: Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior

Entrez PubMed: "It is becoming increasingly apparent that multiple functions of the frontal cortex such as inhibitory control and executive attention are likely sustained by its functionally distinct and interacting sub-regions but the precise localization of dissociable executive processes has proved difficult and controversial. In the present series of studies, we investigated the behavioural effects of bilateral excitotoxic lesions of different regions of the rat neocortex in the 5-choice serial reaction time task. Whereas lesions of the dorsal anterior cingulate cortex (ACC) impaired performance of the task as revealed by a reduction in discriminative accuracy, lesions made to distinct ventral regions of the frontal cortex showed selective deficits in inhibitory measures of control. Specifically, the infralimbic lesion produced increases in premature responding that was accompanied by fast response latencies. By comparison, the orbitofrontal lesion showed perseverative tendencies particularly when the inter-trial interval was made long and unpredictable, a challenge that would normally promote premature responding instead. These different behavioural effects following dorsal and ventral lesions of the rodent frontal cortex signifies the integrity of the frontal cortex in multiple executive mechanisms that work independently and complementarily by which performance is optimized. Furthermore, these data provide new insights into the functional organization of the rodent frontal cortex with a particular emphasis on localization of function."

Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity.
Chudasama Y, Passetti F, Rhodes SE, Lopian D, Desai A, Robbins TW.
Behav Brain Res. 2003 Nov 30;146(1-2):105-19.
Erratum in:
Behav Brain Res. 2004 Jul 9;152(2):453.

ADHD: NEUROSCIENCE OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER: THE SEARCH FOR ENDOPHENOTYPES

Nature Reviews Neuroscience - Reviews: "Research on attention-deficit/hyperactivity disorder (ADHD), a highly prevalent and controversial condition, has, for the most part, been descriptive and atheoretical. The imperative to discover the genetic and environmental risk factors for ADHD is motivating the search for quantifiable intermediate constructs, termed endophenotypes. In this selective review, we conclude that such endophenotypes should be solidly grounded in the neurosciences. We propose that three such endophenotypes -- a specific abnormality in reward-related circuitry that leads to shortened delay gradients, deficits in temporal processing that result in high intrasubject intertrial variability, and deficits in working memory -- are most amenable to integrative collaborative approaches that aim to uncover the causes of ADHD."

F. Xavier Castellanos & Rosemary Tannock
NEUROSCIENCE OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER: THE SEARCH FOR ENDOPHENOTYPES
Nature Reviews Neuroscience 3, 617-628 (2002); doi:10.1038/nrn896

PTSD : PET imaging: Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery.

Entrez PubMed: "Functional neuroimaging experiments targeting personal recall of emotional events may help elucidate neural substrates underlying posttraumatic stress disorder (PTSD). Studies suggest that limbic and paralimbic function might be altered in PTSD, as compared with trauma-exposed control subjects; however, little is known about functional changes resulting from traumatic experience itself. The present study examined both PTSD-specific and trauma-specific regional cerebral blood flow (rCBF) patterns during script-driven imagery. . . Differential patterns of activation were detected in amygdala and medial frontal cortex. Past trauma experience was associated with decreased amygdala activity (i.e., less activity than healthy control subjects); however, combat control subjects deactivated this region (i.e., greater activity to neutral scripts). All subjects deactivated medial frontal cortex; PTSD patients had greater rostral anterior cingulate (rACC) deactivation compared with control groups, who deactivated ventromedial prefrontal cortex (vmPFC). Trauma-specific patterns may represent potential compensatory changes to traumatic reminders, while patterns observed only in the PTSD group may reflect neural substrates specific to PTSD pathophysiology."

Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery.
Britton JC, Phan KL, Taylor SF, Fig LM, Liberzon I.
Biol Psychiatry. 2005 Apr 15;57(8):832-40.

Abuse: Abused Children Stay Highly Attuned To Anger

Abused Children Stay Highly Attuned To Anger: "Even the subtlest hints of anger or hostility in their environment sets physically abused children on prolonged 'alert', even if a conflict has nothing to do with them.

The tendency to stay attentive of nearby discord is probably a natural form of self-preservation in children who routinely face aggression. But it may also explain why abused children are often so distracted at school, write researchers from the University of Wisconsin-Madison, in the journal Child Development (September 14, 2005).

Led by Seth Pollak, a professor of psychology, psychiatry and pediatrics, the UW-Madison team tracked biological markers in 11 abused four and five-year olds who play a computer game in one room when suddenly a clearly audible, heated argument erupts between students next door.
Unbeknownst to the children, the "argument"- over an incomplete homework assignment - was actually a scripted dialogue performed by two actors.

Both abused and non-abused children initially displayed signs of emotional arousal-such as sweaty palms and decelerated heart rates--in reaction to the angry voices in the next room. Heart rates often decelerate prior to a "fight or flight" response, says Pollak, who is also a researcher at the UW-Madison Waisman Center for Human Development.

But though heart rates of non-abused subjects soon rose back to normal levels, heart rates in the abused group remained low-the abused children could not completely break their attention away from the next-door argument, even when it ended peacefully.
"What's really interesting about this experiment is that the abused children were taking their attention resources and redeploying them into something that had nothing to do with the children at all," says Pollak. "That provides an important clue about why these children are having interpersonal problems."

The UW-Madison work builds on past experiments in which Pollak has aimed to understand the developmental mechanisms that may lead abuse victims to adopt unhealthy behaviors later in life, such as aggression, social anxiety and addictions. "Several psychologists had put forward some very sophisticated theories about the outcomes of child abuse but no one had offered any brain-based cognitive models to explain why those outcomes occur," Pollak says.

Consequently, in 1999, Pollak showed that electrical brain activity spikes dramatically when abused children view digital images of angry faces. That result was not too surprising, he says. "Obviously, abused children's brains are doing exactly what they should be doing - they are learning to cope with their situation."

The latest work explores whether abused children react similarly to anger in real life situations, or in this case, experimental simulations of the real world. Pollak says the next step will be to discern exactly which neural systems and brain regions are most affected after physical abuse. "Knowing this specificity could help us figure out ways to eventually intervene in tailored ways.""

Memory: Multiple memory systems: the power of interactions.

Entrez PubMed: "Two relatively simple theories of brain function will be used to demonstrate the explanatory power of multiple memory systems in your brain interacting cooperatively or competitively to directly or indirectly influence cognition and behaviour. The view put forth in this mini-review is that interactions between memory systems produce normal and abnormal manifestations of behaviour, and by logical extension, an understanding of these complex interactions holds the key to understanding debilitating brain and psychiatric disorders."

Multiple memory systems: the power of interactions.
McDonald RJ, Devan BD, Hong NS.
Neurobiol Learn Mem. 2004 Nov;82(3):333-46.

Memory : Multiple memory systems: The power of interactions
Author Keywords: Interactions; Memory; Hippocampus; Dorsal striatum; Amygdala; Prefrontal cortex; Nucleus accumbens; Anxiety; Depression; Fear; Obsessive–compulsive disorder; Schizophrenia; Drug addiction; Drug abuse

NOTE: Despite discussing "multiple memory systems", the authors make no mention of DID in their keywords. This is yet another example of problematic diagnoses leading to erroneous reporting.

Depression: The role of the hippocampus in the pathophysiology of major depression.

Entrez PubMed: "Converging lines of research suggest that the hippocampal complex (HC) may have a role in the pathophysiology of major depressive disorder (MDD). Although postmortem studies show little cellular death in the HC of depressed patients, animal studies suggest that elevated glucocorticoid levels associated with MDD may negatively affect neurogenesis, cause excitotoxic damage or be associated with reduced levels of key neurotrophins in the HC. Antidepressant medications may counter these effects, having been shown to increase HC neurogenesis and levels of brain-derived neurotrophic factor in animal studies. Neuropsychological studies have identified deficits in hippocampus-dependent recollection memory that may not abate with euthymia, and such memory impairment has been the most reliably documented cognitive abnormality in patients with MDD. Finally, data from imaging studies suggest both structural changes in the volume of the HC and functional alterations in frontotemporal and limbic circuits that may be critical for mood regulation. The extent to which such functional and structural changes determine clinical outcome in MDD remains unknown; a related, but also currently unanswered, question is whether the changes in HC function and structure observed in MDD are preventable or modifiable with effective treatment for the depressive illness."

The role of the hippocampus in the pathophysiology of major depression. Campbell S, Macqueen G.
J Psychiatry Neurosci. 2004 Nov;29(6):417-26.

Free Full Text Article

Depression Sleep Disturbance: Neuroanatomic correlates of psychopathologic components of major depressive disorder.

Entrez PubMed: "The Hamilton Depression Rating Scale (HDRS) is widely used to measure the severity of depression in mood disorders. Total HDRS score correlates with brain metabolism as measured by fludeoxyglucose F 18 ([(18)F]-FDG) positron emission tomography. The HDRS comprises distinct symptom clusters that may be associated with different patterns of regional brain glucose metabolism. Total HDRS score correlated positively with activity in a large bilateral ventral cortical and subcortical region that included limbic, thalamic, and basal ganglia structures. Distinct correlation patterns were found with the 3 individual HDRS factors. Psychic depression correlated positively with metabolism in the cingulate gyrus, thalamus, and basal ganglia. Sleep disturbance correlated positively with metabolism in limbic structures and basal ganglia. Loss of motivated behavior was negatively associated with parietal and superior frontal cortical areas. Different brain regions correlate with discrete symptom components that compose the overall syndrome of major depression. Future studies should extend knowledge about specific regional networks by identifying responsible neurotransmitters related to specific psychopathologic components of mood disorders."

Neuroanatomic correlates of psychopathologic components of major depressive disorder.
Milak MS, Parsey RV, Keilp J, Oquendo MA, Malone KM, Mann JJ.
Arch Gen Psychiatry. 2005 Apr;62(4):397-408.

Depression: CBT: Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy.

Entrez PubMed: "Functional imaging studies of major depressive disorder demonstrate response-specific regional changes following various modes of antidepressant treatment. . . Like other antidepressant treatments, CBT (cognitive behaviour therapy) seems to affect clinical recovery by modulating the functioning of specific sites in limbic and cortical regions. Unique directional changes in frontal cortex, cingulate, and hippocampus with CBT relative to paroxetine may reflect modality-specific effects with implications for understanding mechanisms underlying different treatment strategies."

Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy.
Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S, Mayberg H.
Arch Gen Psychiatry. 2004 Jan;61(1):34-41.

Depression: Correlation between cerebral blood flow and items of the Hamilton Rating Scale for Depression in antidepressant-naive patients.

Entrez PubMed: "The purpose of this study was to correlate the basal cerebral blood flow (CBF) in patients with major depressive disorder (MDD) with the score for each of the 21 questions in the Hamilton Rating Scale for Depression (HRSD), in order to determine the cerebral regions associated with each item. . . Items 1, 6, 11 and 20 were positively correlated with right medial frontal gyrus; item 7 was negatively correlated with bilateral medial frontal gyrus. Items 2 and 10 were positively correlated with right anterior and medial cingulate, respectively. Item 5 was negatively correlated with the left amygdala. Item 9 was negatively correlated with bilateral insula, and item 16 with right insula. Items 12 and 14 were positively correlated with right and left precentral frontal gyrus, respectively. Limitations: The small sample size and only out-patients included in the study. CONCLUSIONS: The frontal cortex plays an important role in the expression of MDD symptoms. Not all the symptoms evaluated correlated with one single structure, which may explain the diverse results reported in the literature. These preliminary results support the necessity of further analyses by symptoms that could provide more specific information on the pathophysiology of MDD."

Correlation between cerebral blood flow and items of the Hamilton Rating Scale for Depression in antidepressant-naive patients.
Graff-Guerrero A, Gonzalez-Olvera J, Mendoza-Espinosa Y, Vaugier V, Garcia-Reyna JC.
J Affect Disord. 2004 May;80(1):55-63.

Imaging: Mood Insomnia: Relationship between regional cerebral blood flow and separate symptom clusters of major depression: a single photon emission

Entrez PubMed: "This study examined the relationship between resting regional cerebral blood flow (rCBF) patterns in patients with major depressive disorder (MDD) and specific symptom clusters derived from ratings on the Hamilton Rating Scale for Depression (HRSD) and the Mini Mental State Examination. We hypothesized that the functional activity in frontal, parietal, anterior cingulate, basal ganglia and limbic regions would be related to specific symptom domains. . . Severity of depressive mood was inversely correlated with rCBF in the left amygdala, lentiform nucleus, and parahippocampal gyrus, and directly correlated with rCBF in the right postero-lateral parietal cortex (p < 0.001, uncorrected for multiple comparisons). Insomnia severity was inversely correlated with rCBF in the right rostral and subgenual anterior cingulate cortices, insula and claustrum. Anxiety severity was directly correlated with rCBF in the right antero-lateral orbitofrontal cortex, while cognitive performance was directly correlated with rCBF in the right postero-medial orbitofrontal cortex and in the left lentiform nucleus. Our findings confirmed the prediction that separate symptom domains of the MDD syndrome are related to specific rCBF patterns, and extend results from prior studies that suggested the involvement of anterior cingulate, frontal, limbic and basal ganglia regions in the pathophysiology of MDD."

Relationship between regional cerebral blood flow and separate symptom clusters of major depression: a single photon emission computed tomography study using statistical parametric mapping.
Perico CA, Skaf CR, Yamada A, Duran F, Buchpiguel CA, Castro CC, Soares JC, Busatto GF.
Neurosci Lett. 2005 Aug 26;384(3):265-70.

Depression: Limbic-frontal circuitry in major depression: a path modeling metanalysis.

Entrez PubMed: "This paper reports the results of an across lab metanalysis of effective connectivity in major depression (MDD). Using FDG PET data and Structural Equation Modeling, a formal depression model was created to explicitly test current theories of limbic-cortical dysfunction in MDD and to characterize at the path level potential sources of baseline variability reported in this patient population. A 7-region model consisting of lateral prefrontal cortex (latF9), anterior thalamus (aTh), anterior cingulate (Cg24), subgenual cingulate (Cg25), orbital frontal cortex (OF11), hippocampus (Hc), and medial frontal cortex (mF10) was tested in scans of 119 depressed patients and 42 healthy control subjects acquired during three separate studies at two different institutions. "A single model, based on previous theory and supported by anatomical connectivity literature, was stable for the three groups of depressed patients. Within the context of this model, path differences among groups as a function of treatment response characteristics were also identified. First, limbic-cortical connections (latF9-Cg25-OF11-Hc) differentiated drug treatment responders from nonresponders. Second, nonresponders showed additional abnormalities in limbic-subcortical pathways (aTh-Cg24-Cg25-OF11-Hc). Lastly, more limited limbic-cortical (Hc-latF9) and cortical-cortical (OF11-mF10) path differences differentiated responders to cognitive behavioral therapy (CBT) from responders to pharmacotherapy. We conclude that the creation of such models is a first step toward full characterization of the depression phenotype at the neural systems level, with implications for the future development of brain-based algorithms to determine optimal treatment selection for individual patients."

Limbic-frontal circuitry in major depression: a path modeling metanalysis.
Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, Rafi-Tari S.
Neuroimage. 2004 May;22(1):409-18.

Depression: 5HT: Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients

Entrez PubMed: "The serotonin hypothesis of depression invokes a relative or absolute deficit of serotonin neurotransmission. Reduced synthesis of serotonin in the brain pathways mediating the expression of mood (ie, the limbic cortex) is a plausible candidate mechanism. . . Compared with age- and sex-matched controls, normalized K* was significantly decreased bilaterally in female patients with MD in the anterior cingulate cortex, in the left anterior cingulate cortex in male patients with MD, and in the left mesial temporal cortex in male and female patients with MD (P<.001 for all). Exploratory analyses identified additional patient-control differences for normalized K* (eg, inferior frontal gyrus and superior parietal lobule), most of which, once corrected for 38 multiple comparisons, lost their significance. Morphometric measurements of the cingulate cortex divisions confirmed that the reduction of normalized K* in depressed patients was not attributable to a reduction in gray matter volume. Normalized K* in the anterior cingulate cortex did not correlate with ratings of depression severity collected at the time of scan. CONCLUSIONS: Reduction of normalized K*, an index of serotonin synthesis, in parts of the limbic and paralimbic cortices may contribute to the biochemical alterations associated with MD."

Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression.
Rosa-Neto P, Diksic M, Okazawa H, Leyton M, Ghadirian N, Mzengeza S, Nakai A, Debonnel G, Blier P, Benkelfat C.
Arch Gen Psychiatry. 2004 Jun;61(6):556-63.

Depression: Regional brain serotonin synthesis is increased in the olfactory bulbectomy rat model of depression: an autoradiographic study.

Entrez PubMed: "Serotonin synthesis rates were evaluated using alpha-[14C]methyl-l-tryptophan (alpha-MTrp) autoradiographic methods in olfactory bulbectomized (OBX) rats. They were significantly (p < 0.05) increased in the frontal (50%) and parietal (40%) cortices, superior olive (over 30%), and the substantia nigra (30%) in the OBX rats as compared to the sham operated animals. There were also increases in 5-hydroxytryptamine (5-HT) synthesis in some limbic areas: the cingulate (32%), the medial forebrain bundle (58%), the hippocampus (13-25%) and the thalamus (22-40%). The largest increase in 5-HT synthesis after OBX was observed in the sensory-motor cortex (67%). 5-HT synthesis rates were significantly decreased in the dorsal and medial raphe nuclei, but there was no significant change the ventral tegmental area and the locus coeruleus following OBX. These results indicate that olfactory bulbectomy causes an imbalance in 5-HT synthesis in some projection areas by disproportionally increasing 5-HT synthesis rates in specific brain regions and making more 5-HT available for neurotransmission. This imbalance in 5-HT synthesis and the subsequent elevation of tissue 5-HT may be responsible for the creation of non-physiological circuitry which may, in part, be reflected in the symptoms resembling human depression."

Regional brain serotonin synthesis is increased in the olfactory bulbectomy rat model of depression: an autoradiographic study.
Watanabe A, Tohyama Y, Nguyen KQ, Hasegawa S, Debonnel G, Diksic M.
J Neurochem. 2003 Apr;85(2):469-75.

Depression: rTMS: Acute left prefrontal transcranial magnetic stimulation in depressed patients is associated with immediately increased activity in

Entrez PubMed: "Focal prefrontal cortex repetitive transcranial magnetic stimulation (rTMS) was originally investigated as a potential antidepressant under the assumption that in depressed patients, prefrontal cortex stimulation would produce changes in connected limbic regions involved in mood regulation. . . Over the left prefrontal cortex, 1-Hz TMS was associated with increased activity at the site of stimulation as well as in connected limbic regions: bilateral middle prefrontal cortex, right orbital frontal cortex, left hippocampus, mediodorsal nucleus of the thalamus, bilateral putamen, pulvinar, and insula (t = 3.85, p <.001). Significant deactivation was found in the right ventromedial frontal cortex. CONCLUSIONS: In depressed patients, 1-Hz TMS at 100% motor threshold over the left prefrontal cortex induces activation underneath the coil, activates frontal-subcortical neuronal circuits, and decreases activity in the right ventromedial cortex. Further work is needed to understand whether these immediate changes vary as a function of TMS use parameters (intensity, frequency, location) and whether they relate to neurobiologic effects and antidepressant mechanisms of TMS."

Acute left prefrontal transcranial magnetic stimulation in depressed patients is associated with immediately increased activity in prefrontal cortical as well as subcortical regions.
Li X, Nahas Z, Kozel FA, Anderson B, Bohning DE, George MS.
Biol Psychiatry. 2004 May 1;55(9):882-90.

Depression: Frontolimbic response to negative feedback in clinical depression.

Entrez PubMed: "Functional neuroimaging suggests that limbic regions of the medial frontal cortex may be abnormally active in individuals with depression. These regions, including the anterior cingulate cortex, are engaged in both action regulation, such as monitoring errors and conflict, and affect regulation, such as responding to pain. The authors examined whether clinically depressed subjects would show abnormal sensitivity of frontolimbic networks as they evaluated negative feedback. . . By 350 ms after the feedback signal, depressed subjects showed a larger medial frontal negativity for all feedback compared with control subjects with a particularly striking response to the F grade. This response was strongest for moderately depressed subjects and was attenuated for subjects who were more severely depressed. Localization analyses suggested that negative feedback engaged sources in the anterior cingulate and insular cortices. These results suggest that moderate depression may sensitize limbic networks to respond strongly to aversive events."

Frontolimbic response to negative feedback in clinical depression.
Tucker DM, Luu P, Frishkoff G, Quiring J, Poulsen C.
J Abnorm Psychol. 2003 Nov;112(4):667-78.

Depression: Face emotion perception and executive functioning deficits in depression.

Entrez PubMed: "Frontal, limbic and temporal regions of the brain important in emotion perception and executive functioning also have been implicated in the etiology and maintenance of depression; yet, the relationships among these topics remain poorly understood. The present study evaluated emotion perception and executive functioning among 21 depressed women and 20 nondepressed women controls. Depressed women performed significantly worse than controls in emotion perception accuracy and in inhibitory control, an aspect of executive functioning, whereas the groups did not differ in other cognitive tests assessing memory, visual-spatial, motor, and attention skills. The findings suggest that emotion perception and executive functioning are disproportionately negatively affected relative to other cognitive functions, even in a high-functioning group of mildly depressed women. Measures of emotion perception and executive functioning may be of assistance in objectively measuring functional capability of the ventral and dorsal neural systems, respectively, as well as in the diagnosis of depression."

Face emotion perception and executive functioning deficits in depression.
Langenecker SA, Bieliauskas LA, Rapport LJ, Zubieta JK, Wilde EA, Berent S.
J Clin Exp Neuropsychol. 2005 Apr;27(3):320-33.

Limbic system: The basal ganglia: anatomy, physiology, and pharmacology.

Entrez PubMed: "The basal ganglia are perceived as important nodes in cortico-subcortical networks involved in the transfer, convergence, and processing of information in motor, cognitive, and limbic domains. How this integration might occur remains a matter of some debate, particularly given the consistent finding in anatomic and physiologic studies of functional segregation in cortico-subcortical loops. More recent theories, however, have raised the notion that modality-specific information might be integrated not spatially, but rather temporally, by coincident processing in discrete neuronal populations. Basal ganglia neurotransmitters, given their diverse roles in motor performance, learning, working memory, and reward-related activity are also likely to play an important role in the integration of cerebral activity. Further work will elucidate this to a greater extent, but for now, it is clear that the basal ganglia form an important nexus in the binding of cognitive, limbic, and motor information into thought and action."

The basal ganglia: anatomy, physiology, and pharmacology.
Tisch S, Silberstein P, Limousin-Dowsey P, Jahanshahi M.
Psychiatr Clin North Am. 2004 Dec;27(4):757-99.

Emotion: Limbic system: A review of systems and networks of the limbic forebrain/limbic midbrain.

Entrez PubMed: "Evolutionarily older brain systems, such as the limbic system, appear to serve fundamental aspects of emotional processing and provide relevant and motivational information for phylogenetically more recent brain systems to regulate complex behaviors. Overall, overt behavior is, in part, determined by the interactions of multiple learning and memory systems, some seemingly complementary and some actually competitive. An understanding of limbic system function in emotion and motivation requires that these subsystems be recognized and characterized as extended components of a distributed limbic network. Behavioral neuroscientists face the challenge of teasing apart the contributions of multiple overlapping neuronal systems in order to begin to elucidate the neural mechanisms of the limbic system and their contributions to behavior. One major consideration is to bring together conceptually the functions of individual components of the limbic forebrain and the related limbic midbrain systems. For example, in the rat the heterogeneous regions of the prefrontal cortex (e.g., prelimbic, anterior cingulate, subgenual cortices and orbito-frontal areas) make distinct contributions to emotional and motivational influences on behavior and each needs consideration in its own right. Major interacting structures of the limbic system include the prefrontal cortex, cingulate cortex, amygdaloid nuclear complex, limbic thalamus, hippocampal formation, nucleus accumbens (limbic striatum), anterior hypothalamus, ventral tegmental area and midbrain raphe nuclei; the latter comprising largely serotonergic components of the limbic midbrain system projecting to the forebrain. The posterior limbic midbrain complex comprising the stria medullaris, central gray and dorsal and ventral nuclei of Gudden are also key elements in the limbic midbrain. Some of these formations will be discussed in terms of the neurochemical connectivity between them. We put forward a systems approach in order to build a network model of the limbic forebrain/limbic midbrain system, and the interactions of its major components. In this regard, it is important to keep in mind that the limbic system is both an anatomical entity as well as a physiological concept. We have considered this issue in detail in the introduction to this review. The components of these systems have usually been considered as functional units or 'centers' rather than being components of a larger, interacting, and distributed functional system. In that context, we are oriented toward considerations of distributed neural systems themselves as functional entities in the brain."

A review of systems and networks of the limbic forebrain/limbic midbrain.
Morgane PJ, Galler JR, Mokler DJ.
Prog Neurobiol. 2005 Feb;75(2):143-60.

Fear: Emotional perseveration: an update on prefrontal-amygdala interactions in fear extinction.

Entrez PubMed: "Fear extinction refers to the ability to adapt as situations change by learning to suppress a previously learned fear. This process involves a gradual reduction in the capacity of a fear-conditioned stimulus to elicit fear by presenting the conditioned stimulus repeatedly on its own. Fear extinction is context-dependent and is generally considered to involve the establishment of inhibitory control of the prefrontal cortex over amygdala-based fear processes. In this paper, we review research progress on the neural basis of fear extinction with a focus on the role of the amygdala and the prefrontal cortex. We evaluate two competing hypotheses for how the medial prefrontal cortex inhibits amygdala output. In addition, we present new findings showing that lesions of the basal amygdala do not affect fear extinction. Based on this result, we propose an updated model for integrating hippocampal-based contextual information with prefrontal-amygdala circuitry."

Emotional perseveration: an update on prefrontal-amygdala interactions in fear extinction.
Sotres-Bayon F, Bush DE, LeDoux JE.
Learn Mem. 2004 Sep-Oct;11(5):525-35.

Fear: Building and burying fear memories in the brain.

Entrez PubMed: "The world is a dangerous place. Whether this danger takes the form of an automobile careening toward you or a verbal threat from a stranger, your brain is highly adapted to perceive such threats, organize appropriate defensive behaviors, and record the circumstances surrounding the experience. Indeed, memories of fearful events serve a critical biological function by allowing humans and other animals to anticipate future dangers. But these memories can also feed pathological fear, yielding crippling clinical conditions such as panic disorder. In this review, the author will examine how the brain builds fear memories and how these memories come to be suppressed when they no longer predict danger. The review will focus on the fundamental role for synapses in the amygdala in acquiring fear memories and the function of neural circuits interconnecting the amygdala, hippocampus, and prefrontal cortex in modulating the expression of such memories once learned. The discovery of the neural architecture for fear memory highlights the powerful interplay between animal and human research and the promise for understanding the neurobiological mechanisms of other complex cognitive phenomena."

Building and burying fear memories in the brain.
Maren S.
Neuroscientist. 2005 Feb;11(1):89-99.

Full text requires subsription to "Neuroscientist": http://nro.sagepub.com/cgi/reprint/11/1/89

Threat Response: A direct brainstem-amygdala-cortical 'alarm' system for subliminal signals of fear.

Entrez PubMed: "We examined whether consciously undetected fear signals engage a collateral brainstem pathway to the amygdala and prefrontal cortex in the intact human brain, using functional neuroimaging. 'Blindsight' lesion patients can respond to visual fear signals independently from conscious experience, suggesting that these signals reach the amygdala via a direct pathway that bypasses the primary visual cortex. Electrophysiological evidence points to concomitant involvement of prefrontal regions in automatic orienting to subliminal signals of fear, which may reflect innervation arising from brainstem arousal systems. To approximate blindsight in 22 healthy subjects, facial signals of fear were presented briefly (16.7 ms) and masked such that conscious detection was prevented. Results revealed that subliminal fear signals elicited activity in the brainstem region encompassing the superior colliculus and locus coeruleus, pulvinar and amygdala, and in fronto-temporal regions associated with orienting. These findings suggest that crude sensory input from the superior colliculo-pulvinar visual pathway to the amygdala may allow for sufficient appraisal of fear signals to innervate the locus coeruleus. The engagement of the locus coeruleus could explain the observation of diffuse fronto-temporal cortical activity, given its role in evoking collateral ascending noradrenergic efferents to the subcortical amygdala and prefrontal cortex. This network may represent an evolutionary adaptive neural 'alarm' system for rapid alerting to sources of threat, without the need for conscious appraisal."

A direct brainstem-amygdala-cortical 'alarm' system for subliminal signals of fear.
Liddell BJ, Brown KJ, Kemp AH, Barton MJ, Das P, Peduto A, Gordon E, Williams LM.
Neuroimage. 2005 Jan 1;24(1):235-43.

Fear and the amygdala: manipulation of awareness generates differential cerebral responses to phobic and fear-relevant (but nonfeared) stimuli.

Entrez PubMed: "Rapid response to danger holds an evolutionary advantage. In this positron emission tomography study, phobics were exposed to masked visual stimuli with timings that either allowed awareness or not of either phobic, fear-relevant (e.g., spiders to snake phobics), or neutral images. When the timing did not permit awareness, the amygdala responded to both phobic and fear-relevant stimuli. With time for more elaborate processing, phobic stimuli resulted in an addition of an affective processing network to the amygdala activity, whereas no activity was found in response to fear-relevant stimuli. Also, right prefrontal areas appeared deactivated, comparing aware phobic and fear-relevant conditions. Thus, a shift from top-down control to an affectively driven system optimized for speed was observed in phobic relative to fear-relevant aware processing. "

Carlsson K, Petersson KM, Lundqvist D, Karlsson A, Ingvar M, Ohman A.
Emotion. 2004 Dec;4(4):340-53.

Sociopathy: Fear: Deficient fear conditioning in psychopathy: a functional magnetic resonance imaging study.

Entrez PubMed: "Psychopaths belong to a larger group of persons with antisocial personality disorder and are characterized by an inability to have emotional involvement and by the repeated violation of the rights of others. It was hypothesized that this behavior might be the consequence of deficient fear conditioning.
The healthy controls showed enhanced differential activation in the limbic-prefrontal circuit (amygdala, orbitofrontal cortex, insula, and anterior cingulate) during the acquisition of fear and successful verbal and autonomic conditioning. The psychopaths displayed no significant activity in this circuit and failed to show conditioned skin conductance and emotional valence ratings, although contingency and arousal ratings were normal. CONCLUSION: This dissociation of emotional and cognitive processing may be the neural basis of the lack of anticipation of aversive events in criminal psychopaths."

Birbaumer N, Veit R, Lotze M, Erb M, Hermann C, Grodd W, Flor H.
Deficient fear conditioning in psychopathy: a functional magnetic resonance imaging study.
Arch Gen Psychiatry. 2005 Jul;62(7):799-805.

Fear: Mesolimbic dopaminergic pathways in fear conditioning.

Entrez PubMed: "One of the most common paradigms used to study the biological basis of emotion, as well as of learning and memory, is Pavlovian fear conditioning. In the acquisition phase of a fear conditioning experiment, an emotionally neutral conditioned stimulus (CS)--which can either be a discrete stimulus, such as a tone, or a contextual stimulus, such as a specific environment--is paired with an aversive unconditioned stimulus (US), for example a foot shock. As a result, the CS elicits conditioned fear responses when subsequently presented alone during the expression phase of the experiment. While considerable work has been done in relating specific circuits of the brain to fear conditioning, less is known about its regulation by neuromodulators; the understanding of which would be of therapeutic relevance for fear related diseases such as phobia, panic attacks, post traumatic stress disorder, obsessive compulsive disorder, or generalized anxiety disorder. Dopamine is one of the neuromodulators most potently acting on the mechanisms underlying states of fear and anxiety. Recently, a growing body of evidence has suggested that dopaminergic mechanisms are significant for different aspects of affective memory, namely its formation, expression, retrieval, and extinction. The aim of this review is to clarify the complex actions of dopamine in fear conditioning with respect to the wide-spread distribution of dopaminergic innervation over structures constituting the fear related circuitry. A particular effort is made to understand how dopamine in the amygdala, medial prefrontal cortex and nucleus accumbens--target structures of the mesolimbic dopamine system originating from the ventral tegmental area--could relate to different aspects of fear conditioning."

Mesolimbic dopaminergic pathways in fear conditioning.
Pezze MA, Feldon J.
Prog Neurobiol. 2004 Dec;74(5):301-20.

Fear: Brain activation to phobia-related words in phobic subjects.

Entrez PubMed: "Behavioural studies suggest that phobic subjects are hypersensitive in the processing of phobia-related linguistic stimuli. We used functional magnetic resonance imaging (fMRI) to investigate blood oxygen level dependent (BOLD) brain activation to phobia-relevant words in spider phobic and non-phobic subjects. Phobia-related versus phobia-unrelated words elicited increased activation in prefrontal cortex, insula, and posterior cingulate cortex in spider phobics, while these effects were absent in controls. Furthermore, between-group comparisons confirmed that differential activations within these brain regions were specifically due to increased responses to phobia-related stimuli in phobics. Our results provide first insights into brain activation patterns when phobics are confronted with phobia-specific linguistic information und suggest a neural network for the processing of these threatening stimuli."

Keywords: Phobia; Words; fMRI; Insula; Posterior cingulate gyrus

Brain activation to phobia-related words in phobic subjects.
Straube T, Mentzel HJ, Glauer M, Miltner WH.
Neurosci Lett. 2004 Dec 6;372(3):204-8.

Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.

PsycARTICLES - Behavioral Neuroscience - Vol 106 Iss 2 Page 274: "Lesions of the amygdala interfered with the conditioning of fear responses to both the cue and the context, whereas lesions of the hippocampus interfered with conditioning to the context but not to the cue. The amygdala is thus involved in the conditioning of fear responses to simple, modality-specific conditioned stimuli (CS) as well as to complex, polymodal stimuli, whereas the hippocampus is only involved in fear conditioning situations involving complex, polymodal events. Findings suggest an associative role for the amygdala and a sensory relay role for the hippocampus in fear conditioning. "

This research demonstrates that the amygdala associates the event with the appropriate emotion, while the hippocampus provides a sensory relay for the context of the emotional event.

Emotion: Frontal Cx: Neural substrates of emotion as revealed by functional magnetic resonance imaging.

Entrez PubMed: "Emotional pictures resulted in significantly increased blood flow bilaterally in the mesial frontal lobe/anterior cingulate gyrus, dorsolateral frontal lobe, amygdala/anterior temporal regions, and cerebellum. Negative emotional pictures resulted in greater activation of the right hemisphere, and positive pictures caused greater activation of the left hemisphere."

Neural substrates of emotion as revealed by functional magnetic resonance imaging.
Lee GP, Meador KJ, Loring DW, Allison JD, Brown WS, Paul LK, Pillai JJ, Lavin TB.
Cogn Behav Neurol. 2004 Mar;17(1):9-17.

Aversion: Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter.

Entrez PubMed: "Major depression is conditionally linked to a polymorphism of the human serotonin transporter gene (SLC6A4). During the presentation of aversive, but not pleasant, pictures, healthy carriers of the SLC6A4 short (s) allele showed stronger activation of the amygdala on functional magnetic resonance imaging. s carriers also showed greater coupling between the amygdala and the ventromedial prefrontal cortex, which may contribute to the abnormally high activity in the amygdala and medial prefrontal cortex seen in major depression."

Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter.
Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D, Klein S, Grusser SM, Flor H, Schumann G, Mann K, Buchel C.
Nat Neurosci. 2005 Jan;8(1):20-1. Epub 2004 Dec 12.

Therapy: NIMH: Cognitive Therapy Reduces Repeat Suicide Attempts by 50 Percent

NIMH: Cognitive Therapy Reduces Repeat Suicide Attempts by 50 Percent: "Recent suicide attempters treated with cognitive therapy were 50 percent less likely to try to kill themselves again within 18 months than those who did not receive the therapy, report researchers supported by the National Institutes of Health's (NIH) National Institute of Mental Health (NIMH) and the Center for Disease Control and Prevention (CDC). "

Violence : Influence of bodily harm on neural correlates of semantic and moral decision-making.

Entrez PubMed: "Moral decision-making is central to everyday social life because the evaluation of the actions of another agent or our own actions made with respect to the norms and values guides our behavior in a community. There is previous evidence that the presence of bodily harm--even if irrelevant for a decision--may affect the decision-making process. While recent neuroimaging studies found a common neural substrate of moral decision-making, the role of bodily harm has not been systematically studied so far. Here we used event-related functional magnetic resonance imaging (fMRI) to investigate how behavioral and neural correlates of semantic and moral decision-making processes are modulated by the presence of direct bodily harm or violence in the stimuli. Twelve participants made moral and semantic decisions about sentences describing actions of agents that either contained bodily harm or not and that could easily be judged as being good or bad or correct/incorrect, respectively. During moral and semantic decision-making, the presence of bodily harm resulted in faster response times (RT) and weaker activity in the temporal poles relative to trials devoid of bodily harm/violence, indicating a processing advantage and reduced processing depth for violence-related linguistic stimuli. Notably, there was no increase in activity in the amygdala and the posterior cingulate cortex (PCC) in response to trials containing bodily harm. These findings might be a correlate of limited generation of the semantic and emotional context in the anterior temporal poles during the evaluation of actions of another agent related to violence that is made with respect to the norms and values guiding our behavior in a community."

Influence of bodily harm on neural correlates of semantic and moral decision-making.
Heekeren HR, Wartenburger I, Schmidt H, Prehn K, Schwintowski HP, Villringer A.
Neuroimage. 2005 Feb 1;24(3):887-97. Epub 2004 Nov 26.

Sleep: What can neuroimaging findings tell us about sleep disorders?

Entrez PubMed: "Models of the pathophysiology of human sleep disorders have only recently been tested using nuclear medicine assessments, which have greatly increased our understanding of the brain mechanisms involved in the human sleep-wake cycle. Dramatic changes in function have been observed in large-scale neuronal networks during sleep. Broad declines in heteromodal-association-cortical function, and relative increases in limbic and paralimbic function have been observed. These cortical areas are responsible for essential aspects of human behavior, allowing us to interact with the world around us and to evaluate the significance of important events in our lives. Preliminary findings suggest that fundamental alterations in the function of these neural systems occur in sleep disorders. In depression, alterations in rapid-eye-movement and slow-wave sleep appear linked to a sleep-related dysfunctional arousal in primary limbic and paralimbic structures (amygdala), and hypofunction in frontal cortical areas. Pharmacologic interventions partially reverse these alterations. Preliminary studies in insomia indicate a subcortical hyperarousal and a failure of sleep to provide normal restoration of function in the prefrontal cortex, leading to chronic sleep deprivation. This review discusses functional neuroimaging data on normal sleep, and on the pathophysiology of insomnia related to depression and primary insomnia."

What can neuroimaging findings tell us about sleep disorders?
Nofzinger EA.
Sleep Med. 2004 Jun;5 Suppl 1:S16-22.

ADHD: Impulsivity, emotion regulation, and developmental psychopathology: specificity versus generality of linkages.

Entrez PubMed: "Impulsivity, closely related to the construct of response (dis)inhibition, is central to conceptions of both attention-deficit/hyperactivity (ADHD) and aggressive-spectrum or disruptive behavior disorders. The multifaceted nature of inhibitory deficits requires careful specification in any explanatory accounts of psychopathology. A host of brain regions and neural interconnections are involved in response inhibition; neural models are likely to be complex at the levels of neurotransmitter systems and white-matter tracts. Despite the substantial heritability of ADHD and the substantial continuity of early-onset forms of aggression, developmental processes (including gene-environment correlations and interactions) and transactional models are crucial to the unfolding of regulated versus dysregulated behavioral outcomes. Thus, stressful prenatal and childhood environments must be investigated with as much precision as genetic loci and neural pathways. Differentiating executive inhibition (believed to be largely dopaminergic and frontal/frontal-striatal in nature) from motivational inhibition (believed to be largely noradrenergic/serotonergic and limbic in nature) is necessary to distinguish subtypes of youth with attentional and aggressive problems, and to differentiate key etiologic processes. Indeed, the executive function deficits in children with ADHD appear to independent of their emotion dysregulation, which is specific to an aggressive subgroup. Sex differences in response inhibition and sex differences in its linkages to psychopathology are relatively unexplored. For progress in subsequent research to occur, the following are required: precision in measurement at both biological and behavioral levels; contrasts with clinical comparison samples and comorbid groups (as well as normal control samples); prospective longitudinal investigations; and attention to both developmental processes and contextual variables, including stressful life events, socialization practices, and cultural parameters."

Impulsivity, emotion regulation, and developmental psychopathology: specificity versus generality of linkages.
Hinshaw SP.
Ann N Y Acad Sci. 2003 Dec;1008:149-59.

ADHD: The top and the bottom of ADHD: a neuropsychological perspective.

Entrez PubMed: "Five models of attention deficit/hyperactivity disorder (ADHD) are reviewed. It is proposed that the cognitive-energetic model provides a reasonably comprehensive account of ADHD by incorporating the features of both the inhibition and delay aversion models. It is suggested that ADHD can only be accounted for by an analysis at three levels: top-down control, specific cognitive processes and energetic factors. It is argued that a refined and conceptually comprehensive neuropsychological battery is needed to advance research in ADHD. A widely distributed neural network involving frontal, basal ganglia, limbic and cerebellar loci seem implicated in ADHD."

The top and the bottom of ADHD: a neuropsychological perspective.
Sergeant JA, Geurts H, Huijbregts S, Scheres A, Oosterlaan J.
Neurosci Biobehav Rev. 2003 Nov;27(7):583-92.

ADHD: Response inhibition and disruptive behaviors: toward a multiprocess conception of etiological heterogeneity for ADHD combined type and conduct d

Entrez PubMed: "Response disinhibition is one of several processes that may account for disruptive behavior problems. It is associated with both attention deficits/hyperactivity (ADHD-C) and early onset, unsocialized conduct disorder (CD-E). Response inhibition is not a unitary construct. It is best understood via a dual process model of regulatory control. Executive inhibition refers to deliberate suppression of immediate motor behavior in the service of a distal goal in working memory, with relatively low anxiety activation. It is instantiated in the same frontal-striatal-thalamic neural loops as executive function and corresponds in temperament theory to effortful control. Motivational or reactive inhibition refers to anxiety-provoked interruption of behavior in the context of unexpected, novel, or punishment-cue indicators. Along with reward-response and hostile/angry response it corresponds to reactivity in temperament theory, and invokes limbic responsivity. With regard to these types of inhibitory control, ADHD-combined type is predominantly associated with dysfunctional executive inhibition. CD-E is predominantly associated with dysfunctions in the motivational inhibition process, with smaller, secondary effects in executive control. However, in both syndromes etiological heterogeneity is notable. For example, recent evidence indicates that executive inhibitory control is familial, but characterizes only a subset of children with ADHD-C. Recent dual-process models for both ADHD-C and CD-E are therefore important; they are noted and integrated. Examination of the correlates of behavioral inhibition in the subgroups with these inhibitory deficits may prove fruitful in clarifying the diverse routes to disruptive psychopathology in children."

Response inhibition and disruptive behaviors: toward a multiprocess conception of etiological heterogeneity for ADHD combined type and conduct disorder early-onset type.
Nigg JT.
Ann N Y Acad Sci. 2003 Dec;1008:170-82.

Panic: Tx: PET: The change of regional brain metabolism (18FDG PET) in panic disorder during the treatment with cognitive behavioral therapy or antide

Entrez PubMed: "The goal of our study was to identify brain structures in patients with panic disorder (PD) that show changes in 18FDG PET during the treatment with cognitive behavioral therapy (CBT) or antidepressants. . . The scores of psychopathology rating scales (CGI, HAMA, PDSS) decreased in both groups. Changes of 18FDG uptake in the pharmacotherapy group: decreases were found in the a priori hypothesized regions in the right hemisphere, in the superior, middle, medial and inferior frontal gyrus, superior and middle temporal gyrus, and increases were detected in the a priori hypothesized regions, mainly in the left hemisphere in medial and middle frontal gyrus, superior, middle and transverse temporal gyrus. Changes of 18FDG uptake in the CBT group: decreases were found in the a priori hypothesized regions of the right hemisphere in the inferior temporal gyrus, superior and inferior frontal gyrus, and increases were detected in the a priori hypothesized region, mostly in the left hemisphere: inferior frontal gyrus, middle temporal gyrus and insula. We did not detect changes in 18FDG uptake in the limbic region (hippocampus, parahippocampal gyrus and amygdala). CONCLUSIONS: Changes in brain metabolism (18FDG uptake) after the treatment either with CBT or with antidepressants were similar in number of brain areas, with prominent right-left difference. This is in concordance with the asymmetry of brain activity noted in patients with PD according to previous PET (and SPECT) studies."

The change of regional brain metabolism (18FDG PET) in panic disorder during the treatment with cognitive behavioral therapy or antidepressants.
Prasko J, Horacek J, Zalesky R, Kopecek M, Novak T, Paskova B, Skrdlantova L, Belohlavek O, Hoschl C.
Neuro Endocrinol Lett. 2004 Oct;25(5):340-8.

Panic: [The contribution of brain imaging to the study of panic disorder]

Entrez PubMed: "The present review is aimed to evaluate the recent contribution of brain imaging techniques to the definition of neuroanatomofunctional models of panic disorder (PD). . . The majority of the reviewed studies suggests that a dysfunction of a neural circuit encompassing prefrontal and temporo-limbic cortices is present in PD. A right hemisphere preferential involvement in PD has been shown by several studies. Reviewed neuroimaging studies suggest a dysfunction of frontal and temporo-limbic circuitries in PD. However, those studies cannot be considered conclusive because of several methodological limitations. Longitudinal and multi-modal studies involving larger patient samples, possibly integrated with population-based and genetic studies, would provide more insight into pathophysiological mechanisms of PD."

[The contribution of brain imaging to the study of panic disorder]
Volpe U, Merlotti E, Mucci A, Galderisi S.
Epidemiol Psichiatr Soc. 2004 Oct-Dec;13(4):237-48.

Bipolar : Imaging: Neuropsychological disturbances and cerebral blood flow in bipolar disorder.

Entrez PubMed: "Assessments included the Positive and Negative Symptom Scale, Global Assessment Functioning, Wechsler Adult Intelligence Scale (WAIS), Wisconsin Card Sorting Test (WCST), Stroop test, Trail Making Test (TMT), California Verbal Learning Test (CVLT), Wechsler Memory Scale (WMS) and phonetic verbal fluency/controlled oral word association tests. Single photon emission computed tomography (SPECT) was carried out with the administration of 99mTc-HMPAO. . . Several corrected correlations between neuropsychological function and cerebral blood flow (CBF) were identified: executive function (WCST) and striatal, frontal, temporal, cerebellum, parietal and cingulate CBF; memory (WMS, WAIS-Digits) and striatal, frontal, temporal and parietal CBF; attentional tasks (Stroop) and striatal, temporo-medial and parietal CBF; verbal learning (CVLT) and frontal, posterior temporal, cingulate and occipital CBF; psychomotor disturbances (TMT) and anterior temporal CBF; poorer intelligence performance scores (WAIS-Vocabulary) and cerebellum and parietal CBF. This study confirms the presence of functional disturbances in fronto-subcortical structures, the cerebellum and limbic system in bipolar patients."

Neuropsychological disturbances and cerebral blood flow in bipolar disorder.
Benabarre A, Vieta E, Martinez-Aran A, Garcia-Garcia M, Martin F, Lomena F, Torrent C, Sanchez-Moreno J, Colom F, Reinares M, Brugue E, Valdes M.
Aust N Z J Psychiatry. 2005 Apr;39(4):227-34.

Borderline: Positron emission tomography in female patients with borderline personality disorder.

Entrez PubMed: "The pathology of Borderline personality disorder (BPD) is poorly understood and its biological basis remains largely unknown. One functional brain imaging study using [(18)F]Deoxyglucose-PET previously reported frontal and prefrontal hypometabolism. We studied brain metabolism at baseline in 12 medication-free female patients with BPD without current substance abuse or depression and 12 healthy female controls by [(18)F]Deoxyglucose-PET and statistical parametric mapping. We found significant frontal and prefrontal hypermetabolism in patients with BPD relative to controls as well as significant hypometabolism in the hippocampus and cuneus. This study demonstrated limbic and prefrontal dysfunction under resting conditions in patients with BPD by FDG-PET. Dysfunction in this network of brain regions, which has been implicated in the regulation of emotion, may underlie symptoms of BPD."

Positron emission tomography in female patients with borderline personality disorder.
Juengling FD, Schmahl C, Hesslinger B, Ebert D, Bremner JD, Gostomzyk J, Bohus M, Lieb K.
J Psychiatr Res. 2003 Mar-Apr;37(2):109-15.

Borderline: Frontolimbic brain abnormalities in patients with borderline personality disorder: a volumetric magnetic resonance imaging study.

Entrez PubMed: "Dual frontolimbic brain pathology has been suggested as a possible correlate of impulsivity and aggressive behavior. One previous study reported volume loss of the hippocampus and the amygdala in patients with borderline personality disorder. We measured limbic and prefrontal brain volumes to test the hypothesis that frontolimbic brain pathology might be associated with borderline personality disorder. METHODS: Eight unmedicated female patients with borderline personality disorder and eight matched healthy controls were studied. The volumes of the hippocampus, amygdala, and orbitofrontal, dorsolateral prefrontal, and anterior cingulate cortex were measured in the patients using magnetic resonance imaging volumetry and compared to those obtained in the controls. RESULTS: We found a significant reduction of hippocampal and amygdala volumes in borderline personality disorder. There was a significant 24% reduction of the left orbitofrontal and a 26% reduction of the right anterior cingulate cortex in borderline personality disorder. Only left orbitofrontal volumes correlated significantly with amygdala volumes. CONCLUSIONS: While volume loss of a single brain structure like the hippocampus is quite an unspecific finding in neuropsychiatry, the patterns of volume loss of the amygdala, hippocampus, and left orbitofrontal and right anterior cingulate cortex might differentiate borderline personality disorder from other neuropsychiatric conditions."

Frontolimbic brain abnormalities in patients with borderline personality disorder: a volumetric magnetic resonance imaging study.
Tebartz van Elst L, Hesslinger B, Thiel T, Geiger E, Haegele K, Lemieux L, Lieb K, Bohus M, Hennig J, Ebert D.
Biol Psychiatry. 2003 Jul 15;54(2):163-71.

OCD: Fear: PET: Amygdala activity in obsessive-compulsive disorder with contamination fear: a study with oxygen-15 water positron emission tomography.

Entrez PubMed: "Previous imaging studies of obsessive-compulsive symptom states have implicated frontal-striatal and limbic regions in the pathophysiology of obsessive-compulsive disorder (OCD). Functional imaging studies, however, have yielded inconsistent results, presumably due to methodological differences (patient inclusion criteria, stimulus paradigm, imaging technique, and absence of control groups). . . Main effects of stimulus type (contamination vs. neutral) were found in bilateral occipital cortex in both groups. A significant group interaction effect was observed in the left amygdala reflecting enhanced activity in response to contamination stimuli in OCD patients. Sensitization effects were observed in the right amygdala in the OCD group; these paralleled an increase in levels of distress and obsessionality as well as a decrease in dorsolateral prefrontal activity. The findings of the present study are consistent with the hypothesis of decreased frontal-striatal control of limbic structures, specifically the amygdala, resulting in an inadequate fear response in OCD patients with contamination fear."

Amygdala activity in obsessive-compulsive disorder with contamination fear: a study with oxygen-15 water positron emission tomography.
van den Heuvel OA, Veltman DJ, Groenewegen HJ, Dolan RJ, Cath DC, Boellaard R, Mesina CT, van Balkom AJ, van Oppen P, Witter MP, Lammertsma AA, van Dyck R.
Psychiatry Res. 2004 Dec 30;132(3):225-37.

OCD: Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis.

Entrez PubMed: "Our results support the hypothesis of increased distractibility for irrelevant information in patients with OCD, PD, and hypochondriasis associated with frontal-striatal and limbic involvement compared with controls. Although patients with OCD did not display an attentional bias in behavior relative to controls, there was a clear, specific neural response during color naming OCD-related words, involving mainly ventral brain regions. In contrast, generalized emotional interference effects were found in PD and hypochondriasis, involving ventral and widespread dorsal brain regions, reflecting not only unconscious emotional stimulus processing but also increased cognitive elaboration."

Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis.
van den Heuvel OA, Veltman DJ, Groenewegen HJ, Witter MP, Merkelbach J, Cath DC, van Balkom AJ, van Oppen P, van Dyck R.
Arch Gen Psychiatry. 2005 Aug;62(8):922-33.

OCD: Limbic paroxysmal magnetoencephalographic activity in 12 obsessive-compulsive disorder patients: a new diagnostic finding.

Entrez PubMed We describe frontotemporal paroxysmal rhythmic activity recorded by magnetoencephalography (MEG) in patients with obsessive-compulsive disorder (OCD). . . RESULTS: Two types of MEG activity were observed in patients with OCD: (1) frontotemporal paroxysmal rhythmic activity with low-amplitude spikes (< 1 picoTesla) in 92% (11/12) of patients and (2) intermittent isolated spikes and sharp waves in all patients (12/12). The OCD group had paroxysmal rhythmic MEG activity in the cingulate cortex (12/12), insula (10/12), hippocampus (9/12), temporal superior gyrus and angular and supramarginal gyri (9/12), precentral and post-central gyri (8/12), orbitofrontal cortex (5/12), and parietal lobes (5/12). MEG recordings were normal in the control group, and EEG findings were normal in both the OCD and control groups. CONCLUSIONS: Frontotemporal paroxysmal rhythmic activity with a preferential limbic distribution is a sensitive MEG finding in patients with OCD. Although the pathophysiology of this abnormality remains unknown, a corticostriatal network dysfunction was hypothesized."

Limbic paroxysmal magnetoencephalographic activity in 12 obsessive-compulsive disorder patients: a new diagnostic finding.
Amo C, Quesney LF, Ortiz T, Maestu F, Fernandez A, Lopez-Ibor MI, Lopez-Ibor JJ.
J Clin Psychiatry. 2004 Feb;65(2):156-62.

Schizophrenia: Optimized voxel-based morphometry of gray matter volume in first-episode, antipsychotic-naive schizophrenia.

Entrez PubMed: "This study examined gray matter (GM) volume abnormalities in first-episode, antipsychotic-naive Indian schizophrenia patients. Magnetic resonance images of 18 schizophrenia patients and 18 matched healthy comparison subjects were analyzed by optimized voxel-based morphometry. Schizophrenia patients had significantly smaller global GM and greater global CSF volumes and smaller regional GM volume in superior frontal, inferior frontal, cingulate, post-central, superior temporal and parahippocampal gyri, inferior parietal lobule, insula, caudate nuclei, thalamus and cerebellum. Findings suggest limbic, heteromodal cortical, striatal, thalamic and cerebellar abnormalities in schizophrenia."

Optimized voxel-based morphometry of gray matter volume in first-episode, antipsychotic-naive schizophrenia.
Jayakumar PN, Venkatasubramanian G, Gangadhar BN, Janakiramaiah N, Keshavan MS.
Prog Neuropsychopharmacol Biol Psychiatry. 2005 May;29(4):587-91. Epub 2005 Apr 13.

Schizophrenia: Morphological brain changes associated with Schneider's first-rank symptoms in schizophrenia: a MRI study.

Entrez PubMed: "Schneider's first-rank symptoms involve an alienated feature of the sense of one's own mental or physical activity. To clarify the brain morphological basis for the production of these symptoms, volumes of the frontal and medial temporal regions and their clinical correlates were examined in patients with schizophrenia. . . Patients had significantly decreased volumes in the cingulate gray matter and the amygdala compared to controls. In the patient group, Schneiderian symptom severity showed significant inverse correlations with volumes of the right posterior cingulate gray matter and of the left anterior parahippocampal gyrus. Schneiderian symptoms may be associated with morphological abnormalities in the limbic-paralimbic regions such as the cingulate gyrus and parahippocampal gyrus, which possibly serve the self-monitoring function and the coherent storage and reactivation of information.
"

Morphological brain changes associated with Schneider's first-rank symptoms in schizophrenia: a MRI study.
Suzuki M, Zhou SY, Hagino H, Niu L, Takahashi T, Kawasaki Y, Matsui M, Seto H, Ono T, Kurachi M.
Psychol Med. 2005 Apr;35(4):549-60.

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Schizophrenia: Scent of a disorder: olfactory functioning in schizophrenia.

Entrez PubMed: "The use of olfactory probes to assess frontal and temporal-limbic system functioning in patients with schizophrenia has garnered increasing interest among basic and clinical investigators. Deficits in odor identification, detection threshold sensitivity, discrimination, and memory have been reported and are thought to represent a centrally mediated deficit in the processing of this information. These impairments are seen in affected probands, first-degree family members, and those at risk for developing the illness, suggesting a genetic vulnerability or predisposition to chemosensory abnormalities. The observed deficits are not explained by gender, medication use, cognitive impairment, or smoking status, and support the hypothesis of primary dysfunction in the olfactory system. Along this same line, structural abnormalities in the peripheral and central olfactory brain regions, as well as disruptions of the basic physiology of this system, have been described. The study of olfactory processing in schizophrenia has already advanced the knowledge of the neural substrate for this disorder. Because the olfactory system continuously regenerates throughout life, it allows for a unique view of an ongoing neurodevelopmental process."

Scent of a disorder: olfactory functioning in schizophrenia.
Moberg PJ, Turetsky BI.
Curr Psychiatry Rep. 2003 Aug;5(4):311-9.

Schizophrenia: Neural correlates of episodic encoding and recognition of words in unmedicated patients during an acute episode of schizophrenia: a fun

Entrez PubMed: "Memory impairment has been well documented in schizophrenia. In a previous study, the authors investigated patterns of brain activity during episodic encoding and recognition of words in remitted, stable schizophrenia outpatients being treated with novel antipsychotics. The same procedure was used in this study to investigate unmedicated patients during an acute episode of schizophrenia. METHOD: Functional magnetic resonance imaging was used to study regional brain activation in 10 unmedicated patients experiencing an acute episode of schizophrenia and 10 healthy comparison subjects during performance of a modified version of the words subtest of Warrington's Recognition Memory Test. RESULTS: Despite intact recognition performance, patients with schizophrenia showed reduced activation of anterior prefrontal, posterior cingulate, and retrosplenial areas relative to comparison subjects during word encoding. During word recognition, reduced activation was found in the patients' dorsolateral prefrontal and limbic/paralimbic regions. On the other hand, higher metabolism in bilateral anterior prefrontal cortices was observed. CONCLUSIONS: The results suggest that different neural pathways are engaged during episodic encoding and recognition of words in patients experiencing an acute episode of schizophrenia relative to healthy comparison subjects. Furthermore, acute psychosis may prevent practice effects, reflected in a failure to engage brain regions associated with successful episodic memory retrieval in healthy subjects."

Neural correlates of episodic encoding and recognition of words in unmedicated patients during an acute episode of schizophrenia: a functional MRI study.
Hofer A, Weiss EM, Golaszewski SM, Siedentopf CM, Brinkhoff C, Kremser C, Felber S, Fleischhacker WW.
Am J Psychiatry. 2003 Oct;160(10):1802-8.

Schizophrenia: Effects of NMDA-receptor antagonist treatment on c-fos expression in rat brain areas implicated in schizophrenia.

Entrez PubMed: "1. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists produce behavioral responses that closely resemble both positive and negative symptoms of schizophrenia. These drugs also induce excitatory and neurotoxic effects in limbic cortical areas. . . 4. MK801 induced c-fos mRNA expression of in the retrosplenial, entorhinal, and prefrontal cortices. Lower c-fos expression was observed in the layer IV of the parietal and frontal cortex. In the thalamus, c-fos mRNA expression was detected in the midline nuclei and in the reticular nucleus but not in the dorsomedial nucleus. In addition, c-fos mRNA was expressed in the anterior olfactory nucleus, the ventral tegmental area, and in cerebellar granule neurons. 5. NMDA-receptor antagonist ketamine increased dopamine release in the parietal cortex, in the region where NMDA-receptor antagonist increased c-fos mRNA expression. 6. Thus, the psychotropic NMDA-receptor antagonist induced c-fos mRNA expression in most, but not all, brain areas implicated in the pathophysiology of schizophrenia. The high spatial resolution of in situ hybridization may help to define regions of interest for human imaging studies."

Effects of NMDA-receptor antagonist treatment on c-fos expression in rat brain areas implicated in schizophrenia.
Vaisanen J, Ihalainen J, Tanila H, Castren E.
Cell Mol Neurobiol. 2004 Dec;24(6):769-80.

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Anxiolytics:Glutamate: Blockade of the mGlu5 receptor decreases basal and stress-induced cortical norepinephrine in rodents.

Entrez PubMed: "Glutamate, the major excitatory neurotransmitter in the brain mediates its effects by both ionotropic and metabotropic receptor subtypes. Recently, the search for selective ligands for glutamate receptor subtypes has led to the discovery of 2-methyl-6-(phenylethynyl)pyridine (MPEP), an antagonist specific for metabotropic glutamate receptor 5 (mGlu5). This receptor is highly expressed in limbic forebrain regions and is thought to modulate anxiety-related processes. The noradrenergic nucleus locus coeruleus (LC) is an important mediator of stress responses and dysfunction of this system is implicated in affective disorders such as anxiety and depression. . . Blockade of the mGlu5 receptor elicited significant reductions in extracellular NE in the frontal cortex. The benzodiazepine diazepam also reduced cortical NE. Furthermore, MPEP administration attenuated stress-induced increases in extracellular NE. Taken together, these data show that MPEP and MTEP, through their blockade of the mGlu5, reduce extracellular norepinephrine, the impact of which may contribute to their anxiolytic actions."

Blockade of the mGlu5 receptor decreases basal and stress-induced cortical norepinephrine in rodents.
Page ME, Szeliga P, Gasparini F, Cryan JF.
Psychopharmacology (Berl). 2005 Apr;179(1):240-6. Epub 2005 Feb 17.

Psychosurgery: Tourette's: Surgery in Tourette syndrome.

Entrez PubMed: "Tourette syndrome (TS) is a neuropsychiatric disorder with onset in early childhood. It is characterized by tics and often accompanied by disturbances in behavior, such as obsessive-compulsive disorder (OCD). In most cases, the disorder is self-limited or can be treated by medication or behavioral therapy. In a small percentage, however, symptoms are intractable to any conservative treatment. Since 1955, various attempts have been made to treat these patients through neurosurgical procedures. The target sites have been diverse and include the frontal lobe (prefrontal lobotomy and bimedial frontal leucotomy), the limbic system (limbic leucotomy and anterior cingulotomy), the thalamus, and the cerebellum. Combined approaches have also been tried such as anterior cingulotomies plus infrathalamic lesions. The results have often been unsatisfactory or major side effects have occurred, such as hemiplegia or dystonia. Our review of the literature from 1960 until 2003 revealed 21 reports and 3 descriptions in textbooks covering about 65 patients in total who had undergone ablative procedures for intractable TS, the first being reported in 1962. In 1999, deep brain stimulation (DBS) was introduced as a new approach for intractable TS. To date, 3 patients have been reported who underwent bilateral thalamic stimulation, with promising results on tics and obsessive-compulsive symptoms."

Surgery in Tourette syndrome.
Temel Y, Visser-Vandewalle V.
Mov Disord. 2004 Jan;19(1):3-14.

Tx: Psychosurgery for self-injurious behavior in Tourette's disorder.

Entrez PubMed: "One of the most serious and difficult-to-treat conditions in child and adolescent psychiatry is self-injurious behavior (SIB). SIB can be associated with a number of psychiatric disorders, including mental retardation, schizophrenia, borderline personality disorder, pervasive developmental disorders, stereotypic movement disorder, and Tourette's Disorder. A variety of neurosurgical procedures have been used to treat both intractable SIB and severe Tourette's Disorder. Understandably, there are few reports concerning psychosurgery in children and adolescents for any condition or disorder. This report describes the use of cingulotomy and subsequent limbic leucotomy in an adolescent boy with Tourette's Disorder for SIB. His repetitive and medically serious SIB and failure of all other treatments prompted this intervention after careful, comprehensive review and discussion. Following the second surgery, the severity and frequency of his SIB were reduced."

Psychosurgery for self-injurious behavior in Tourette's disorder.
Anandan S, Wigg CL, Thomas CR, Coffey B.
J Child Adolesc Psychopharmacol. 2004 Winter;14(4):531-8.

Tx: Psychosurgery: past, present, and future.

Entrez PubMed: "Psychosurgery, the neurosurgical treatment of psychiatric disease, has a history dating back to antiquity, and involves all of the clinical neurosciences. This review discusses the history of psychosurgery, its development in the 19th century, and the conditions of its use and abuse in the 20th century, with a particular focus on the frontal lobotomy. The transition to the modern era of psychosurgery is discussed, as well as the neurobiology underlying current psychosurgical procedures. The techniques of stereotactic cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leukotomy are described, as well their indications and side effects. Due to the past abuse of psychosurgery, procedures are currently under strict control, and the example of the Cingulotomy Committee at the Massachusetts General Hospital is discussed. Finally, future directions of psychosurgery and somatic therapies are explored, including transcranial magnetic stimulation, vagal nerve stimulation, deep brain stimulation, gene therapy, and stem cell therapy. In summary, this review provides a concise yet comprehensive introduction to the history, current practice, and future trends of neurosurgery for psychiatric disorders."

Psychosurgery: past, present, and future.
Mashour GA, Walker EE, Martuza RL.
Brain Res Brain Res Rev. 2005 Jun;48(3):409-19.

Genes: 5HT: Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism.

Entrez PubMed: "Allelic variants in the promoter region of the serotonin transporter (5-HTT) gene have been implicated in several psychiatric disorders and personality traits. In particular, two common alleles in a variable repeat sequence of the promoter region (SLC6A4) have been differentially associated with a display of abnormal levels of anxiety and affective illness in individuals carrying the 's' allele. "

Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism.
Graff-Guerrero A, De la Fuente-Sandoval C, Camarena B, Gomez-Martin D, Apiquian R, Fresan A, Aguilar A, Mendez-Nunez JC, Escalona-Huerta C, Drucker-Colin R, Nicolini H.
Neuroimage. 2005 May 1;25(4):1197-204.

Imaging: Emotion: The neural bases of amusement and sadness: a comparison of block contrast and subject-specific emotion intensity regression approach

Entrez PubMed: "For sad films, both block contrast and subject-specific regression approaches resulted in activations in medial prefrontal cortex, inferior frontal gyrus, superior temporal gyrus, precuneus, lingual gyrus, amygdala, and thalamus. For amusing films, the subject-specific regression analysis demonstrated significant activations not detected by the block contrast in medial, inferior frontal gyrus, dorsolateral prefrontal cortex, posterior cingulate, temporal lobes, hippocampus, thalamus, and caudate. These results suggest a relationship between emotion-specific temporal dynamics and the sensitivity of different data analytic methods for identifying emotion-related neural responses. These findings shed light on the neural bases of amusement and sadness, and highlight the value of using emotional film stimuli and subject-specific continuous emotion ratings to characterize the dynamic, time-varying components of emotional responses."

The neural bases of amusement and sadness: a comparison of block contrast and subject-specific emotion intensity regression approaches.
Goldin PR, Hutcherson CA, Ochsner KN, Glover GH, Gabrieli JD, Gross JJ.
Neuroimage. 2005 Aug 1;27(1):26-36.

Imaging: Emotion: A common neural basis for receptive and expressive communication of pleasant facial affect.

Entrez PubMed: "There is accumulating evidence suggesting that the visual representation of facial affect is closely linked to its motor representation. To examine whether perception of pleasant facial affect involves neural circuitries associated with its production, we performed an fMRI experiment with 'compressed image acquisition' where subjects smiled and observed movies depicting other people smiling within scan-free time intervals between the acquisition of each image volume. Overlaps between the brain activation during observation and execution of smile expressions were located in the right premotor cortex and pars opercularis of the inferior frontal gyrus, right parietal operculum (SII) and left anterior insula. Observation of smile expressions further yielded signal increases within the posterior superior temporal sulcus (STS), fusiform gyrus and ventral amygdala. The results show that perceiving and expressing pleasant facial affect share a common neural basis in areas concerned with motor as well as somato- and limbic-sensory processing. In concert with temporal regions serving the visual analysis of facial expressive features, a mapping of the observed expressions onto neural circuitries associated with the production of these expressions and its somatosensory consequences could provide a description of what the expression would feel like if produced in the observer. Such a mechanism is suggested to be important for empathic understanding of others' feelings."

A common neural basis for receptive and expressive communication of pleasant facial affect.
Hennenlotter A, Schroeder U, Erhard P, Castrop F, Haslinger B, Stoecker D, Lange KW, Ceballos-Baumann AO.
Neuroimage. 2005 Jun;26(2):581-91. Epub 2005 Mar 21.

Anorexia Bulimia: Serotonin alterations in anorexia and bulimia nervosa: new insights from imaging studies.

Entrez PubMed: "Anorexia nervosa (AN) and bulimia nervosa (BN) are related disorders with relatively homogenous presentations such as age of onset and gender distribution. In addition, they share symptoms, such as extremes of food consumption, body image distortion, anxiety and obsessions, and ego-syntonic neglect, raises the possibility that these symptoms reflect disturbed brain function that contributes to the pathophysiology of this illness. Recent brain imaging studies have identified altered activity in frontal, cingulate, temporal, and parietal cortical regions in AN and BN. Importantly, such disturbances are present when subjects are ill and persist after recovery, suggesting that these may be traits that are independent of the state of the illness. Emerging data point to a dysregulation of serotonin pathways in cortical and limbic structures that may be related to anxiety, behavioral inhibition, and body image distortions. In specific, recent studies using PET with serotonin specific radioligands implicate alterations of 5-HT1A and 5-HT2A receptors and the 5-HT transporter. Alterations of these circuits may affect mood and impulse control as well as the motivating and hedonic aspects of feeding behavior. Such imaging studies may offer insights into new pharmacology and psychotherapy approaches."

Serotonin alterations in anorexia and bulimia nervosa: new insights from imaging studies.
Kaye WH, Frank GK, Bailer UF, Henry SE, Meltzer CC, Price JC, Mathis CA, Wagner A.
Physiol Behav. 2005 May 19;85(1):73-81.

Anorexia: Early-onset anorexia nervosa: is there evidence of limbic system imbalance?

Entrez PubMed: "OBJECTIVE: This study, part of a continuing effort to understand the pathophysiology of the brain in early-onset anorexia nervosa, attempts to validate findings from an earlier study of regional cerebral blood flow and to correlate any abnormalities in blood flow with eating disorder psychopathology. METHOD: Fifteen newly referred children and adolescents with a diagnosis of anorexia nervosa (AN) underwent regional cerebral blood flow (rCBF) examination using single-photon computerized tomography (SPECT) and the Eating Disorders Examination (EDE) for children. RESULTS: Mean age was 14 years 11 months (SD = 1.35). Mean weight for height ratio was 82.79 % (SD = 10.66). SPECT findings showed that 11 (73%) had asymmetry (hypoperfusion) of blood flow in at least one area. Regions of the brain showing hypoperfusion included the temporal lobe (n = 9), parietal lobe (n = 5), frontal lobe (n = 3), thalamus (n = 3), and the caudate nuclei (n = 1). The median EDE subscale scores were high for all four subscales. Those patients with hypoperfusion had higher median EDE subscale scores than those without hypoperfusion, although the differences were not statistically significant. CONCLUSIONS: Most patients in our study had abnormal rCBF, predominantly affecting the temporal lobe, confirming our previous findings. There was no association with the EDE scores. The findings support earlier suggestions of an imbalance in neural pathways or circuits, possibly within the limbic system. This hypothesis is considered within the context of current knowledge and suggestions made with regard to how it might be tested.
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Early-onset anorexia nervosa: is there evidence of limbic system imbalance?
Chowdhury U, Gordon I, Lask B, Watkins B, Watt H, Christie D.
Int J Eat Disord. 2003 May;33(4):388-96.

Addiction: Brain damage and addictive behavior: a neuropsychological and electroencephalogram investigation with pathologic gamblers.

Entrez PubMed: "Gambling is a form of nonsubstance addiction classified as an impulse control disorder. Pathologic gamblers are considered healthy with respect to their cognitive status. Lesions of the frontolimbic systems, mostly of the right hemisphere, are associated with addictive behavior. Because gamblers are not regarded as 'brain-lesioned' and gambling is nontoxic, gambling is a model to test whether addicted 'healthy' people are relatively impaired in frontolimbic neuropsychological functions. METHODS: Twenty-one nonsubstance dependent gamblers and nineteen healthy subjects underwent a behavioral neurologic interview centered on incidence, origin, and symptoms of possible brain damage, a neuropsychological examination, and an electroencephalogram. RESULTS: Seventeen gamblers (81%) had a positive medical history for brain damage (mainly traumatic head injury, pre- or perinatal complications). The gamblers, compared with the controls, were significantly more impaired in concentration, memory, and executive functions, and evidenced a higher prevalence of non-right-handedness (43%) and, non-left-hemisphere language dominance (52%). Electroencephalogram (EEG) revealed dysfunctional activity in 65% of the gamblers, compared with 26% of controls. CONCLUSIONS: This study shows that the "healthy" gamblers are indeed brain-damaged. Compared with a matched control population, pathologic gamblers evidenced more brain injuries, more fronto-temporo-limbic neuropsychological dysfunctions and more EEG abnormalities. The authors thus conjecture that addictive gambling may be a consequence of brain damage, especially of the frontolimbic systems, a finding that may well have medicolegal consequences."

Brain damage and addictive behavior: a neuropsychological and electroencephalogram investigation with pathologic gamblers.
Regard M, Knoch D, Gutling E, Landis T.
Cogn Behav Neurol. 2003 Mar;16(1):47-53.

Addiction: Gambling urges in pathological gambling: a functional magnetic resonance imaging study.

Entrez PubMed: "Gambling urges in pathological gambling (PG) often immediately precede engagement in self-destructive gambling behavior. An improved understanding of the neural correlates of gambling urges in PG would advance our understanding of the brain mechanisms underlying PG and would help direct research into effective treatments. METHODS: Echoplanar functional magnetic resonance imaging was used to assess brain function during viewing of videotaped scenarios with gambling, happy, or sad content. Participants rated the quality and magnitude of their emotional and motivational responses. RESULTS: Men with PG (n = 10) reported mean +/- SD greater gambling urges after viewing gambling scenarios vs control subjects (n = 11) (5.20 +/- 3.43 vs 0.32 +/- 0.60; chi21,19 = 21.71; P<.001). The groups did not differ significantly in their subjective responses to the happy (P =.56) or sad (P =.81) videotapes. The most pronounced between-group differences in neural activities were observed during the initial period of viewing of the gambling scenarios: PG subjects displayed relatively decreased activity in frontal and orbitofrontal cortex, caudate/basal ganglia, and thalamus compared with controls. Distinct patterns of regional brain activity were observed in specific temporal epochs of videotape viewing. For example, differences localized to the ventral anterior cingulate during the final period of gambling videotape viewing, corresponding to the presentation of the most provocative gambling stimuli. Although group differences in brain activity were observed during viewing of the sad and happy scenarios, they were distinct from those corresponding to the gambling scenarios. CONCLUSIONS: In men with PG, gambling cue presentation elicits gambling urges and leads to a temporally dynamic pattern of brain activity changes in frontal, paralimbic, and limbic brain structures. When viewing gambling cues, PG subjects demonstrate relatively decreased activity in brain regions implicated in impulse regulation compared with controls."

Gambling urges in pathological gambling: a functional magnetic resonance imaging study.
Potenza MN, Steinberg MA, Skudlarski P, Fulbright RK, Lacadie CM, Wilber MK, Rounsaville BJ, Gore JC, Wexler BE.
Arch Gen Psychiatry. 2003 Aug;60(8):828-36.

Stress: Medial prefrontal cortical integration of psychological stress in rats.

Entrez PubMed: "These results indicate that, during acute psychological stress, the mPFC does not modulate the cardiovascular system in rats but does inhibit specific subcortical nuclei to exert control over aspects of an integrated response to a stressor."

Medial prefrontal cortical integration of psychological stress in rats.
McDougall SJ, Widdop RE, Lawrence AJ.
Eur J Neurosci. 2004 Nov;20(9):2430-40.

Stress: Induction of deltaFosB in reward-related brain structures after chronic stress.

Entrez PubMed: "Acute and chronic stress differentially regulate immediate-early gene (IEG) expression in the brain. Although acute stress induces c-Fos and FosB, repeated exposure to stress desensitizes the c-Fos response, but FosB-like immunoreactivity remains high. Several other treatments differentially regulate IEG expression in a similar manner after acute versus chronic exposure. The form of FosB that persists after these chronic treatments has been identified as DeltaFosB, a splice variant of the fosB gene. . . By use of immunohistochemistry, we found that chronic restraint stress induced DeltaFosB expression predominantly in the fCTX, NAc, and basolateral amygdala, with lower levels of induction seen elsewhere. These findings establish that chronic stress induces DeltaFosB in several discrete regions of the brain. Such induction could contribute to the long-term effects of stress on the brain.
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Induction of deltaFosB in reward-related brain structures after chronic stress.
Perrotti LI, Hadeishi Y, Ulery PG, Barrot M, Monteggia L, Duman RS, Nestler EJ.
J Neurosci. 2004 Nov 24;24(47):10594-602.