SignificanceAll spoken languages express words by sound patterns, and certain sound patterns (e.g.,blog) are systematically preferred to others (e.g.,lbog). However, whether those preferences reflect abstract rules or the motor difficulties associated with speech production is unknown. We address this question using transcranial magnetic stimulation and functional MRI. Results show that speech perception automatically engages the articulatory motor system, but linguistic preferences persist even when the motor system is disrupted. These findings suggest that, despite their intimate links, the language and motor systems are distinct. Language is designed to optimize motor action, but its knowledge includes principles that are disembodied and potentially abstract.

In this study, healthy volunteers were scanned using functional magnetic resonance imaging (fMRI) to investigate the neural systems involved in processing the threatening content conveyed via visually presented "threat words." The neural responses elicited by these words were compared to those elicited by matched neutral control words. The results demonstrate that linguistic threat, when presented in written form, can selectively engage areas of lateral temporal and inferior frontal cortex, distinct from the core language areas implicated in aphasia. Additionally, linguistic threat modulates neural activity in visceral/emotional systems (amygdala, parahippocampal gyrus and periaqueductal gray), and at earlier stages of the visual-linguistic processing stream involved in visual word form representations (ventral occipitotemporal cortex). We propose a model whereby limbic activation modulates activity at multiple nodes along the visual-linguistic-semantic processing stream, including a perisylvian "semantic access network" involved in decoding word meaning, suggesting a dynamic interplay between feedforward and feedback processes. (C) 2015 Elsevier Inc. All rights reserved.

Adaptive behavior requires neural systems that mediate the evaluation of stimuli in terms of the well-being of the organism and generate subsequent goal-directed behavior. The authors provide an overview of these systems, with an emphasis on those related to positive motivation/approach. The authors outline the contributions of various disciplines to the current understanding of these systems and discuss their dysfunction in the context of multiple neuropsychiatric disorders in terms of deficits, dysregulation, excess, and related syndromes. Illustrative examples are provided, with an emphasis on functional neuroimaging studies. This approach can provide a foundation for conceptualization, diagnosis, and targeted neuromodulatory therapeutics of neuropsychiatric disorders.

AimsBorderline personality disorder (BPD) is characterized by self‐regulation deficits, including impulsivity and affective lability. Transference‐focused psychotherapy (TFP) is an evidence‐based treatment proven to reduce symptoms across multiple cognitive–emotional domains in BPD. This pilot study aimed to investigate neural activation associated with, and predictive of, clinical improvement in emotional and behavioral regulation in BPD following TFP.MethodsBPD subjects (n = 10) were scanned pre‐ and post‐TFP treatment using a within‐subjects design. A disorder‐specific emotional–linguistic go/no‐go functional magnetic resonance imaging paradigm was used to probe the interaction between negative emotional processing and inhibitory control.ResultsAnalyses demonstrated significant treatment‐related effects with relative increased dorsal prefrontal (dorsal anterior cingulate, dorsolateral prefrontal, and frontopolar cortices) activation, and relative decreased ventrolateral prefrontal cortex and hippocampal activation following treatment. Clinical improvement in constraint correlated positively with relative increased left dorsal anterior cingulate cortex activation. Clinical improvement in affective lability correlated positively with left posterior‐medial orbitofrontal cortex/ventral striatum activation, and negatively with right amygdala/parahippocampal activation. Post‐treatment improvements in constraint were predicted by pre‐treatment right dorsal anterior cingulate cortex hypoactivation, and pre‐treatment left posterior‐medial orbitofrontal cortex/ventral striatum hypoactivation predicted improvements in affective lability.ConclusionsThese preliminary findings demonstrate potential TFP‐associated alterations in frontolimbic circuitry and begin to identify neural mechanisms associated with a psychodynamically oriented psychotherapy.

Persecutory delusions are a clinically important symptom in schizophrenia associated with social avoidance and increased violence. Few studies have investigated the neurobiology of persecutory delusions, which is a prerequisite for developing novel treatments. The aim of this two-paradigm functional magnetic resonance imaging (fMRI) study is to characterize social “real world” and linguistic threat brain activations linked to persecutory delusions in schizophrenia (n=26) using instructed-fear/safety and emotional word paradigms. Instructed-fear/safety activations correlated to persecutory delusion severity demonstrated significant increased lateral orbitofrontal cortex and visual association cortex activations for the instructed-fear vs. safety and instructed-fear vs. baseline contrasts; decreased lateral orbitofrontal cortex and ventral occipital-temporal cortex activations were observed for the instructed-safety stimuli vs. baseline contrast. The salience network also showed divergent fear and safety cued activations correlated to persecutory delusions. Emotional word paradigm analyses showed positive correlations between persecutory delusion severity and left-lateralized linguistic and hippocampal–parahippocampal activations for the threat vs. neutral word contrast. Visual word form area activations correlated positively with persecutory delusions for both threat and neutral word vs. baseline contrasts. This study links persecutory delusions to enhanced neural processing of threatening stimuli and decreased processing of safety cues, and helps elucidate systems-level activations associated with persecutory delusions in schizophrenia.

Back to table of contents Previous article Next article LettersFull AccessSuccessful Treatment of Dopamine Dysregulation Syndrome With Valproic AcidJane Epstein, M.D., Carolina Jimenez Madiedo, M.D., Leonard Lai, M.D., and Michael T. Hayes, M.D.Jane Epstein, M.D., Carolina Jimenez Madiedo, M.D., Leonard Lai, M.D., and Michael T. Hayes, M.D.Published Online:1 Jul 2014https://doi.org/10.1176/appi.neuropsych.13060126AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Dopamine dysregulation syndrome (DDS) is a maladaptive behavioral pattern of excessive and compulsive seeking of dopamine replacement therapy (DRT) beyond what is necessary to control motor symptoms of Parkinson's Disease (PD).1 In addition to behaviors related to drug seeking, it can involve aggressive, hypomanic, impulsive, and compulsive behaviors associated with excessive use of DRT; and dysphoria and anxiety associated with withdrawal states. Although various management strategies have been explored, no clearly effective treatment has been established.2,3 Recently, Sriram et al4 published a consecutive case series of four patients successfully treated for DDS with valproic acid. We present an additional case of successful treatment using this approach.The patient was a 62-year-old woman with a 10 year-history of PD and no past history of psychiatric or substance related disorders, who developed DDS in the year following addition of levodopa/carbidopa to her treatment regimen. She became preoccupied with the medication, hoarding it, and taking increasingly frequent doses despite developing uncomfortable dyskinesias. When her husband tried to limit her medication usage, she became impatient, anxious, irritable, and argumentative, at one point even reporting him to the police. She developed periods of mania, hallucinations, impulsive shopping, and compulsive arranging of picture frames, or "punding." These alternated with periods of intense dysphoria, anhedonia, anxiety, panic attacks, and suicidal ideation. Prior to visiting our neuropsychiatry clinic, the patient had undergone psychiatric treatment, including two hospitalizations, involving multiple medication trials and ECT, with poor response. In addition, she had begun to overuse the prescribed psychotropics, which at the time of her visit, included sertraline, quetiapine, and lorazepam. On neuropsychiatric evaluation, she received the diagnosis of DDS, and arrangements were made for admission to our inpatient psychiatric unit with close neurologic consultation.In the inpatient unit, the patient was started on divalproex sodium extended release, initially at a dose of 250 mg, with increase to 500 mg q.h.s. Her sinemet regimen was closely regulated on a fixed schedule. Her sertraline was stopped, quietiapine regulated, and lorazepam regulated and tapered. She and her husband received education regarding DDS and associated symptoms. Over the course of 2 weeks, the patient manifested a decrease in preoccupation with her medications and parkinsonian symptoms, and a stabilization of mood, affect, sleep, and behavior. No compulsive or impulsive behaviors were observed. She was discharged to home with her husband, who had bought a locked, programmable medication dispenser at the recommendation of the treatment team. On outpatient follow-up 2 weeks post-discharge, the patient displayed continued improvement. Her husband had stopped locking the medication dispenser, as she was no longer seeking extra doses. These gains were maintained at 1-month follow-up.In conclusion, our case essentially represents a fifth consecutive instance of successful treatment of DDS with valproic acid, as reported by Sriram et al.4 Although the mechanism(s) of action remain unclear,4 this relatively rapid and striking improvement in an additional patient is heartening, given the extensive morbidity associated with this syndrome, and the lack of consistently effective existing treatments.Department of Psychiatry, Brigham and Women's Hospital, Boston, MADepartment of Psychiatry, Brigham and Women's Faulkner Hospital, Boston, MADepartment of Neurology, Brigham and Women's Hospital, Boston, MASend correspondence to Dr. Epstein; e-mail: [email protected]orgThe authors report no financial relationships with commercial interests.References1 Giovannoni G, O'Sullivan JD, Turner K, et al.: Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry 2000; 68:423–428Crossref, Medline, Google Scholar2 Katzenschlager R: Dopaminergic dysregulation syndrome in Parkinson's disease. J Neurol Sci 2011; 310:271–275Crossref, Medline, Google Scholar3 Cilia R, Siri C, Canesi M, et al.: Dopamine dysregulation syndrome in Parkinson's disease: from clinical and neuropsychological characterisation to management and long-term outcome. J Neurol Neurosurg Psychiatry 2014; 85:311–318Crossref, Medline, Google Scholar4 Sriram A, Ward HE, Hassan A, et al.: Valproate as a treatment for dopamine dysregulation syndrome (DDS) in Parkinson's disease. J Neurol 2013; 260:521–527Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byExpert Review of Neurotherapeutics, Vol. 19, No. 10European Journal of Neuroscience, Vol. 45, No. 1Current Neurology and Neuroscience Reports, Vol. 16, No. 5Expert Review of Neurotherapeutics, Vol. 16, No. 4Prolonged neuropsychiatric effects following management of chloroquine intoxication with psychotropic polypharmacy9 April 2015 | Clinical Case Reports, Vol. 3, No. 6Levodopa/carbidopa30 August 2014 | Reactions Weekly, Vol. 1516, No. 1 Volume 26Issue 3 Summer 2014Pages E3-E3 Metrics PDF download History Published online 1 July 2014 Published in print 1 July 2014

It is well known that natural languages share certain aspects of their design. For example, across languages, syllables like blif are preferred to lbif. But whether language universals are myths or mentally active constraints-linguistic or otherwise-remains controversial. To address this question, we used fMRI to investigate brain response to four syllable types, arrayed on their linguistic well-formedness (e.g., blif≻bnif≻bdif≻lbif, where ≻ indicates preference). Results showed that syllable structure monotonically modulated hemodynamic response in Broca's area, and its pattern mirrored participants' behavioral preferences. In contrast, ill-formed syllables did not systematically tax sensorimotor regions-while such syllables engaged primary auditory cortex, they tended to deactivate (rather than engage) articulatory motor regions. The convergence between the cross-linguistic preferences and English participants' hemodynamic and behavioral responses is remarkable given that most of these syllables are unattested in their language. We conclude that human brains encode broad restrictions on syllable structure.

Back to table of contents Previous article Next article LettersFull AccessA Case of Cotard Syndrome in a Woman With a Right Subdural HemorrhageDavid L. Perez, M.D., Benjamin H. Fuchs, B.A., and Jane Epstein, M.D.David L. Perez, M.D., Benjamin H. Fuchs, B.A., and Jane Epstein, M.D.Published Online:1 Jan 2014https://doi.org/10.1176/appi.neuropsych.13020021AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Délire des négations (nihilistic syndrome) was first described in 1880 by Jules Cotard in a woman with a psychotic depression.1 Cotard syndrome is a rare neuropsychiatric condition involving the delusional belief that one has died or is dying, and it includes nihilistic thoughts of specific body parts or self-related themes. We present a case of Cotard syndrome after a spontaneous right frontoparietal subdural hemorrhage.Case ReportA 73-year-old, right-handed, Caucasian woman with no previous neuropsychiatric history presented to a tertiary-care psychiatric emergency room insisting that she was "going to die and going to hell." This belief started abruptly overnight when she woke her husband to express matter-of-factly that she had "gotten on in years" and her "time to pass away would arrive shortly." This belief persisted for 48 hours, prompting a visit to the emergency room. On interview, she denied low mood or other symptoms of depression. She had no history of affective or psychotic disorders, head trauma, or seizures. Her medical history was notable for hypothyroidism and hypertension treated with levothyroxine 100 mcg and antihypertensive medications; she was not on antiplatelet medications. She had a family history of depression, with a maternal uncle who had committed suicide. Mental status examination revealed flat affect, linear thought process, and thought content notable for preoccupation with her impending death. She was alert and fully oriented. She correctly spelled "world" backward, and made one error in reciting the months of the year in reverse order. Repetition, naming, and expressive and receptive language were normal. Ideomotor praxis was intact. She registered 3/3 words and recalled 1/3 words in 5 minutes, and did not benefit from categorical prompts. Vital signs and neurological exam were unremarkable, including the absence of long track signs and a lack of extinction to double simultaneous visual or tactile stimulation. Laboratory studies showed normal electrolytes, blood counts, liver function, and coagulation profiles; thyroid stimulating hormone was 3.63 μU/ml. Head computed tomography (CT) revealed an acute-on-chronic, 12-mm right fronto-parietal subdural hemorrhage. Electroencephalography demonstrated near continuous theta slowing over the right hemisphere, maximal in the frontotemporal region, without epileptiform activity. She was started on levetiracetam 500 mg twice daily and admitted for 24 hours to the neurology inpatient ward. Follow-up CT was unchanged, and her nihilistic delusion resolved within 1 week.DiscussionCotard syndrome has been previously described in idiopathic psychiatric conditions including schizophrenia and psychotic depression2 and across neurologic disorders, including cerebral infarctions, traumatic brain injury, arteriovenous malformations, multiple sclerosis, and neurodegenerative diseases.3 This case highlights the finding that Cotard syndrome may present after subdural hemorrhage with disruption of nondominant fronto-parieto-temporal networks, consistent with previously-reported lesion sites.3,4 Right temporoparietal dysfunction has been implicated in disorders of corporeal awareness.5 Preserved left hemisphere-mediated interpreter functions, together with right-hemispheric dysfunction and frontal executive impairments, may contribute to the development of false nihilistic beliefs.Functional Neuroimaging Laboratory, Brigham and Women's Hospital, Boston, MA (DLP, BHF, JE)Dept. of Psychiatry, Brigham and Women's Hospital, Boston, MA (DLP, JE)Dept. of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA (DLP)Dept. of Neurology, Brigham and Women's Hospital, Boston, MA (DLP)Correspondence: Dr. Perez; e-mail: david.lperez@gmail.comAn abstract of this case was accepted for poster presentation at the 2013 American Neuropsychiatric Association meeting in Boston, MA.References1 Cotard J: Du délire hypocondriaque dans une forme grave de la melancolie anxieuse. Ann Med Psychol (Paris) 1880; 4:168–174Google Scholar2 Ramirez-Bermudez J, Aguilar-Venegas LC, Crail-Melendez D, et al.: Cotard syndrome in neurological and psychiatric patients. J Neuropsychiatry Clin Neurosci 2010; 22:409–416Link, Google Scholar3 Kudler SNCGS, Jaimon M: An overview of the neurological correlates of Cotard syndrome. Eur J Psychiatry 2007; 21:99–116Google Scholar4 Young AW, Robertson IH, Hellawell DJ, et al.: Cotard delusion after brain injury. Psychol Med 1992; 22:799–804Crossref, Medline, Google Scholar5 Devinsky O: Right cerebral hemisphere dominance for a sense of corporeal and emotional self. Epilepsy Behav 2000; 1:60–73Crossref, Google Scholar FiguresReferencesCited byDetailsCited byCotard Syndrome Misdiagnosed as Major Depressive Disorder31 May 2023A medical algorithm for Cotard delusion based on more than 300 literature cases16 September 2020 | International Journal of Psychiatry in Clinical Practice, Vol. 25, No. 3Depresión psicótica y síndrome de Cotard en una paciente con enfermedad de Graves-Basedow: reporte de un casoPsiquiatría Biológica, Vol. 28, No. 2The 'dead man walking' disorder: an update on Cotard's syndrome5 June 2020 | International Review of Psychiatry, Vol. 32, No. 5-6Estructura factorial del Síndrome de Cotard: revisión sistemática de reportes de casoRevista Colombiana de Psiquiatría, Vol. 49, No. 3Factor structure of Cotard's syndrome: Systematic review of case reportsRevista Colombiana de Psiquiatría (English ed.), Vol. 49, No. 3International Journal of Psychiatry in Clinical Practice, Vol. 23, No. 2A Neuropsychiatric Analysis of the Cotard DelusionAradhana Sahoo, B.S., Keith A. Josephs, M.D.23 June 2017 | The Journal of Neuropsychiatry and Clinical Neurosciences, Vol. 30, No. 1Case Reports in Medicine, Vol. 2016Cotard's Syndrome in a Patient with Schizophrenia: Case Report and Review of the LiteratureCase Reports in Psychiatry, Vol. 2016An Integrative Neurocircuit Perspective on Psychogenic Nonepileptic Seizures and Functional Movement Disorders27 November 2014 | Clinical EEG and Neuroscience, Vol. 46, No. 1 Volume 26Issue 1 Winter 2014Pages E29-E30 Metrics An abstract of this case was accepted for poster presentation at the 2013 American Neuropsychiatric Association meeting in Boston, MA.PDF download History Published online 1 January 2014 Published in print 1 January 2014

Psychosis is a devastating, prevalent condition considered to involve dysfunction of frontal and medial temporal limbic brain regions as key nodes in distributed brain networks involved in emotional regulation. The psychoses of epilepsy represent an important, though understudied, model relevant to understanding the pathophysiology of psychosis in general. In this review, we (1) discuss the classification of epilepsy-related psychoses and relevant neuroimaging and other studies; (2) review structural and functional neuroimaging studies of schizophrenia focusing on evidence of frontal-limbic dysfunction; (3) report our laboratory's PET, fMRI, and electrophysiological findings; (4) describe a theoretical framework in which frontal hypoactivity and intermittent medial temporal hyperactivity play a critical role in the etiopathology of psychosis both associated and unassociated with epilepsy; and (5) suggest avenues for future research.

Most functional neuroimaging studies of major depressive disorder (MDD) employ univariate methods of statistical analysis to localize abnormalities of neural activity. Less has been done to investigate functional relations between these regions, or with regions not usually implicated in depression. Examination of intraneuronal and interneural network relations is important for the advancement of emerging network models for MDD. Principal component analysis (PCA), a multivariate statistical method, was used to examine differences in functional connectivity between 10 unmedicated patients with MDD and 12 healthy subjects engaged in a positive word viewing task. In healthy subjects, principal component (PC) 1 (33% variance) revealed functional connectivity of task-specific sensory, linguistic, and motor regions, along with functional anticorrelations in the default mode network; PC2 (10% variance) displayed functional connectivity of areas involved in emotional processing. This segregation of functions did not occur in the depressed group, where regions involved in emotional functions appeared in PC1 (34% variance) co-varying with those involved in linguistic, motor, and default mode network processing. The lack of segregation of emotional processing from cognitive and sensorimotor functions may represent a systems level neural substrate for a core phenomenon of depression: the interconnection of affective disturbance with experience, cognition, and behavior.

Neurosurgical treatment of psychiatric disorders has been influenced by evolving neurobiological models of symptom generation. The advent of functional neuroimaging and advances in the neurosciences have revolutionized understanding of the functional neuroanatomy of psychiatric disorders. This article reviews neuroimaging studies of depression from the last 3 decades and describes an emerging neurocircuitry model of mood disorders, focusing on critical circuits of cognition and emotion, particularly those networks involved in the regulation of evaluative, expressive and experiential aspects of emotion. The relevance of this model for neurotherapeutics is discussed, as well as the role of functional neuroimaging of psychiatric disorders.

This article provides a survey of major methodological and analytic developments in the use of functional neuroimaging to study complex structural and functional brain activity and connectivity, including data analysis methods devised to distill network properties from high-dimensional and multimodal datasets. The goal of this survey is to provide those in the broader neuroscientific community with an understanding of these developments sufficient to facilitate an informed reading of the literature, and a thoughtful approach to their use in the investigation of questions in their own areas of interest. Practical methodological considerations for assessing and designing functional neuroimaging studies are provided, as are examples of the types of questions that can be addressed by various techniques.

Abstract The reorganization of the adult central nervous system after damage is a relatively new area of investigation. Neuroimaging methods, such as functional magnetic resonance imaging, diffusion tensor imaging, and positron emission tomography, have the ability to identify, in vivo, some of the processes involved in these neuroplastic changes and can help with diagnosis, prognosis, and potentially treatment approaches. In this article, traumatic brain injury and stroke are used as examples in which neural plasticity plays an important role in recovery. Basic concepts related to brain remodeling, including spontaneous reorganization and training-induced recovery, as well as characteristics of reorganization in successful recovery, are reviewed. The microscopic and molecular mechanisms that underlie neural plasticity and neurogenesis are briefly described. Finally, exciting future directions for the evaluation, diagnosis, and treatment of severe brain injury are explored, with an emphasis on how neuroimaging can help to inform these new approaches.

The development and exacerbation of many psychiatric and neurologic conditions are associated with dysregulation of the hypothalamic pituitary adrenal (HPA) axis as measured by aberrant levels of cortisol secretion. Here we report on the relationship between the amplitude of diurnal cortisol secretion, measured across 3 typical days in 18 healthy individuals, and blood oxygen level dependant (BOLD) response in limbic fear/stress circuits, elicited by in-scanner presentation of emotionally negative stimuli, specifically, images of the World Trade Center (WTC) attack. Results indicate that subjects who secrete a greater amplitude of cortisol diurnally demonstrate less brain activation in limbic regions, including the amygdala and hippocampus/parahippocampus, and hypothalamus during exposure to traumatic WTC-related images. Such initial findings can begin to link our understanding, in humans, of the relationship between the diurnal amplitude of a hormone integral to the stress response, and those neuroanatomical regions that are implicated as both modulating and being modulated by that response.

Frontolimbic structures involved in fear conditioning have also been associated with hypothalamic-pituitary-adrenal (HPA)-axis modulation, including amygdaloid, hippocampal, and ventromedial prefrontal cortex regions. Although HPA-axis function and endocrine changes have been investigated in the context of stress provocation, much research has not been conducted using functional neuroimaging in the study of the HPA axis and frontolimbic function in response to emotional stimuli. Using functional magnetic resonance imaging, the association of blood-oxygen-level dependent signal with salivary cortisol in response to an emotional visual scene paradigm was investigated, with prescan and postscan salivary cortisol analyzed as a covariate of interest during specific conditions. Cortisol reactivity to the paradigm was positively associated with amygdalar and hippocampal activity and negatively associated with ventromedial prefrontal cortex activity in conditions involving emotional imagery.

Background: Premenstrual dysphoric disorder (PMDD) is a prevalent disorder in the spectrum of affective illness, and is associated with significant morbidity. The neurobiology of this underdiagnosed and undertreated illness is poorly understood. A functional magnetic resonance imaging (fMRI) probe of fronto-limbic function was used to advance understanding of PMDD pathophysiology.Methods: We applied BOLD fMRI and Statistical Parametric Mapping to study neural response to emotional words in the context of an emotional Go/NoGo inhibitory control task. We examined alterations in this response across the menstrual cycle, in the premenstrual (late luteal) phase and the postmenstrual (late follicular) phase.Results: In the premenstrual (vs. postmenstrual) phase, PMDD subjects, compared with asymptomatic subjects, showed an increased amygdala response to negative vs. neutral stimuli, and a decreased ventral striatum response to positive vs. neutral stimuli. PMDD subjects failed to show the asymptomatic subjects' patterns of increased medial and decreased lateral orbitofrontal cortex (OFC) response to negative vs. neutral stimuli in the premenstrual vs. postmenstrual phase. This decreased premenstrual medial OFC response to negative stimuli in PMDD subjects was further enhanced in the context of behavioral inhibition.Limitations: Further studies with larger numbers of subjects are needed.Conclusions: The results support a neurobiological model of enhanced negative emotional processing, diminished positive emotional processing, and diminished top-down control of limbic activity in PMDD during the premenstrual phase. These findings provide a basis for a neurocircuitry model of PMDD, and have implications for studies of mood/emotional regulation across the human menstrual cycle in health and disease. (C) 2007 Elsevier B.V. All rights reserved.