Haggai Sharon

Diminished language lateralization in schizophrenia corresponds to impaired inter-hemispheric functional connectivity

INTRODUCTION A consistent brain imaging finding in schizophrenia is decreased language-asymmetry, already evident in first episode patients, thus arguing for a biomarker of the disorder. Nonetheless, its specificity to schizophrenia is questionable. Furthermore, while previous studies suggested that enhanced right hemisphere activation underlies this diminished asymmetry, the mechanism for this anomaly is yet unknown. This study aimed to examine the role of inter-hemispheric relations in such abnormality through functional connectivity analysis driven by left inferior frontal gyrus (IFG) activation. To test for disorder specificity we compared schizophrenia patients not only to healthy controls but also to patients with obsessive compulsive disorder (OCD). METHODS Functional magnetic resonance imaging (fMRI) was applied during an auditory verb generation task in the 3 groups. Language-related activation in BA44/45 located in the IFG was used for regional estimation of brain asymmetry and for assessment of inter-hemispheric functional connectivity. RESULTS Schizophrenia, but not OCD patients showed reduced language asymmetry in the IFG relative to healthy controls and diminished functional connectivity between the left and right IFG. Importantly, decreased inter-hemispheric functional connectivity in the IFG was related to more negative symptoms among the schizophrenia patients. CONCLUSIONS Diminished language-related asymmetry in the IFG seems to be an early disorder specific neural marker of schizophrenia, supporting its pathogenic role. The relation of this regional abnormality to reduced inter-hemispheric functional connectivity and symptom severity supports the role of large-scale brain disorganization in schizophrenia. This may relate to the known structural abnormalities of the corpus callosum leading to functional hemispheric dysconnection.

Losing Neutrality: The Neural Basis of Impaired Emotional Control without Sleep

Sleep deprivation has been shown recently to alter emotional processing possibly associated with reduced frontal regulation. Such impairments can ultimately fail adaptive attempts to regulate emotional processing (also known as cognitive control of emotion), although this hypothesis has not been examined directly. Therefore, we explored the influence of sleep deprivation on the human brain using two different cognitive–emotional tasks, recorded using fMRI and EEG. Both tasks involved irrelevant emotional and neutral distractors presented during a competing cognitive challenge, thus creating a continuous demand for regulating emotional processing. Results reveal that, although participants showed enhanced limbic and electrophysiological reactions to emotional distractors regardless of their sleep state, they were specifically unable to ignore neutral distracting information after sleep deprivation. As a consequence, sleep deprivation resulted in similar processing of neutral and negative distractors, thus disabling accurate emotional discrimination. As expected, these findings were further associated with a decrease in prefrontal connectivity patterns in both EEG and fMRI signals, reflecting a profound decline in cognitive control of emotion. Notably, such a decline was associated with lower REM sleep amounts, supporting a role for REM sleep in overnight emotional processing. Altogether, our findings suggest that losing sleep alters emotional reactivity by lowering the threshold for emotional activation, leading to a maladaptive loss of emotional neutrality. SIGNIFICANCE STATEMENT Sleep loss is known as a robust modulator of emotional reactivity, leading to increased anxiety and stress elicited by seemingly minor triggers. In this work, we aimed to portray the neural basis of these emotional impairments and their possible association with frontal regulation of emotional processing, also known as cognitive control of emotion. Using specifically suited EEG and fMRI tasks, we were able to show that sleep deprivation alters emotional reactivity by triggering enhanced processing of stimuli regarded previously as neutral. These changes were further accompanied by diminished frontal connectivity, reduced REM sleep, and poorer performance. Therefore, we suggest that sleep loss alters emotional reactivity by lowering the threshold for emotional activation, leading to a maladaptive loss of emotional neutrality.

Emotional Processing of Personally Familiar Faces in the Vegetative State

Background The Vegetative State (VS) is a severe disorder of consciousness in which patients are awake but display no signs of awareness. Yet, recent functional magnetic resonance imaging (fMRI) studies have demonstrated evidence for covert awareness in VS patients by recording specific brain activations during a cognitive task. However, the possible existence of incommunicable subjective emotional experiences in VS patients remains largely unexplored. This study aimed to probe the question of whether VS patients retain a brain ability to selectively process external stimuli according to their emotional value and look for evidence of covert emotional awareness in patients. Methods and Findings In order to explore these questions we employed the emotive impact of observing personally familiar faces, known to provoke specific perceptual as well as emotional brain activations. Four VS patients and thirteen healthy controls first underwent an fMRI scan while viewing pictures of non-familiar faces, personally familiar faces and pictures of themselves. In a subsequent imagery task participants were asked to actively imagine one of their parents faces. Analyses focused on face and familiarity selective regional brain activations and inter-regional functional connectivity. Similar to controls, all patients displayed face selective brain responses with further limbic and cortical activations elicited by familiar faces. In patients as well as controls, Connectivity was observed between emotional, visual and face specific areas, suggesting aware emotional perception. This connectivity was strongest in the two patients who later recovered. Notably, these two patients also displayed selective amygdala activation during familiar face imagery, with one further exhibiting face selective activations, indistinguishable from healthy controls. Conclusions Taken together, these results show that selective emotional processing can be elicited in VS patients both by external emotionally salient stimuli and by internal cognitive processes, suggesting the ability for covert emotional awareness of self and the environment in VS patients.

Neuro-Epigenetic Indications of Acute Stress Response in Humans: The Case of MicroRNA-29c

Stress research has progressively become more integrative in nature, seeking to unfold crucial relations between the different phenotypic levels of stress manifestations. This study sought to unravel stress-induced variations in expression of human microRNAs sampled in peripheral blood mononuclear cells and further assess their relationship with neuronal and psychological indices. We obtained blood samples from 49 healthy male participants before and three hours after performing a social stress task, while undergoing functional magnetic resonance imaging (fMRI). A seed-based functional connectivity (FC) analysis was conducted for the ventro-medial prefrontal cortex (vmPFC), a key area of stress regulation. Out of hundreds of microRNAs, a specific increase was identified in microRNA-29c (miR-29c) expression, corresponding with both the experience of sustained stress via self-reports, and alterations in vmPFC functional connectivity. Explicitly, miR-29c expression levels corresponded with both increased connectivity of the vmPFC with the anterior insula (aIns), and decreased connectivity of the vmPFC with the left dorso-lateral prefrontal cortex (dlPFC). Our findings further revealed that miR-29c mediates an indirect path linking enhanced vmPFC-aIns connectivity during stress with subsequent experiences of sustained stress. The correlative patterns of miR-29c expression and vmPFC FC, along with the mediating effects on subjective stress sustainment and the presumed localization of miR-29c in astrocytes, together point to an intriguing assumption; miR-29c may serve as a biomarker in the blood for stress-induced functional neural alterations reflecting regulatory processes. Such a multi-level model may hold the key for future personalized intervention in stress psychopathology.

Neurofunctional view of psychiatry: clinical brain imaging revisited.

Purpose of review Despite an exponential increase in the use of brain imaging in neuroscience, it has as yet hardly been integrated into clinical psychiatry. Our aim is to examine the potentials and perspectives of functional brain imaging in the diagnosis and treatment of mental disorders. Recent findings This review focuses on functional MRI in probing neural activation and on diffusion tensor imaging in delineating functionally related fibre-track organization. As a case study, it examines the state-of-the-art in applying these methods in schizophrenia by referring to several hurdles in the common clinical practice of psychiatry. First, we evaluate the ability of functional brain imaging to target various neuropathological mechanisms such as neurodegeneration, disrupted development and dysconnection. Then we discuss the use of brain-imaging genomics in identifying disease-specific genetic-based neuroendophenotypes. Lastly, we describe the current effort in using brain imaging to designate the most effective and least adverse treatment for patients with schizophrenia. Summary By examining the use of advanced MRI techniques in schizophrenia, we show both the remarkable variety of functional inferences, as well as their possible implications in clinical psychiatry. We advocate the need for extending the view on neuropathology from region-based to network-based, for integrating neurogenomic features as biological markers for illness definition and for relying on neural parameters to guide effective individual treatment.

Detailed behavioral assessment promotes accurate diagnosis in patients with disorders of consciousness

INTRODUCTION Assessing the awareness level in patients with disorders of consciousness (DOC) is made on the basis of exhibited behaviors. However, since motor signs of awareness (i.e., non-reflex motor responses) can be very subtle, differentiating the vegetative from minimally conscious states (which is in itself not clear-cut) is often challenging. Even the careful clinician relying on standardized scales may arrive at a wrong diagnosis. AIM To report our experience in tackling this problem by using two in-house use assessment procedures developed at Reuth Rehabilitation Hospital, and demonstrate their clinical significance by reviewing two cases. METHODS (1) Reuth DOC Response Assessment (RDOC-RA) -administered in addition to the standardized tools, and emphasizes the importance of assessing a wide range of motor responses. In our experience, in some patients the only evidence for awareness may be a private specific movement that is not assessed by standard assessment tools. (2) Reuth DOC Periodic Intervention Model (RDOC-PIM) - current literature regarding assessment and diagnosis in DOC refers mostly to the acute phase of up to 1 year post injury. However, we have found major changes in responsiveness occurring 1 year or more post-injury in many patients. Therefore, we conduct periodic assessments at predetermined times points to ensure patients are not misdiagnosed or neurological changes overlooked. RESULTS In the first case the RDOC-RA promoted a more accurate diagnosis than that based on standardized scales alone. The second case shows how the RDOC-PIM allowed us to recognize late recovery and promoted reinstatement of treatment with good results. CONCLUSION Adding a detailed periodic assessment of DOC patients to existing scales can yield critical information, promoting better diagnosis, treatment, and clinical outcomes. We discuss the implications of this observation for the future development and validation of assessment tools in DOC patients.

I think therefore I am: Rest-related prefrontal cortex neural activity is involved in generating the sense of self.

The sense of self has always been a major focus in the psychophysical debate. It has been argued that this complex ongoing internal sense cannot be explained by any physical measure and therefore substantiates a mind-body differentiation. Recently, however, neuro-imaging studies have associated self-referential spontaneous thought, a core-element of the ongoing sense of self, with synchronous neural activations during rest in the medial prefrontal cortex (PFC), as well as the medial and lateral parietal cortices. By applying deep transcranial magnetic stimulation (TMS) over human PFC before rest, we disrupted activity in this neural circuitry thereby inducing reports of lowered self-awareness and strong feelings of dissociation. This effect was not found with standard or sham TMS, or when stimulation was followed by a task instead of rest. These findings demonstrate for the first time a critical, causal role of intact rest-related PFC activity patterns in enabling integrated, enduring, self-referential mental processing.

Moods as ups and downs of the motivation pendulum: revisiting reinforcement sensitivity theory (RST) in bipolar disorder

Motivation is a key neurobehavioral concept underlying adaptive responses to environmental incentives and threats. As such, dysregulation of motivational processes may be critical in the formation of abnormal behavioral patterns/tendencies. According to the long standing model of the Reinforcement Sensitivity Theory (RST), motivation behaviors are driven by three neurobehavioral systems mediating the sensitivity to punishment, reward or goal-conflict. Corresponding to current neurobehavioral theories in psychiatry, this theory links abnormal motivational drives to abnormal behavior; viewing depression and mania as two abnormal extremes of reward driven processes leading to either under or over approach tendencies, respectively. We revisit the RST framework in the context of bipolar disorder (BD) and challenge this concept by suggesting that dysregulated interactions of both punishment and reward related processes better account for the psychological and neural abnormalities observed in BD. We further present an integrative model positing that the three parallel motivation systems currently proposed by the RST model, can be viewed as subsystems in a large-scale neurobehavioral network of motivational decision making.

Does Co-Morbid Obsessive–Compulsive Disorder Modify the Abnormal Language Processing in Schizophrenia Patients? An fMRI Study

Background: Impaired language processing is one of the most replicated findings in functional brain studies of schizophrenia (SCH). This is demonstrated by reduced activations in left prefrontal language areas (i.e., BA44/45, the inferior frontal gyrus, IFG) presented as decreased language lateralization. This finding was documented both in chronic as well as in first-episode SCH patients, arguing for a neurobiological marker for SCH. In a previous study, we demonstrated the specificity of this finding to SCH patients when compared to obsessive–compulsive disorder (OCD) patients in whom language processing was similar to healthy controls. Since a sizable proportion of SCH patients also meet DSM-IV criteria for OCD, we further sought to elucidate whether OCD attenuates abnormal prefrontal language lateralization in this unique group of schizo-obsessive patients compared to their non-OCD-SCH counterparts. Methods: We used functional magnetic resonance imaging (fMRI) to investigate regional activation and language lateralization in the left and right IFG and inter-hemispheric functional connectivity (FC) during a language task of auditory verb generation in 14 SCH patients with OCD, compared to 17 SCH patients without OCD, 13 OCD patients and 14 healthy controls. Results: No between-group differences were found in the behavioral measurements of word generation. However, while OCD patients were indistinguishable from healthy volunteers, a similarly reduced lateralization in the IFG and diminished inter-hemispheric FC was noted in the two SCH groups with and without OCD. Conclusion: The co-occurrence of OCD in SCH does not attenuate abnormal processing of language as reflected by regional IFG activity and FC. These results further support the notion that these language processing abnormalities are characteristic of SCH and that SCH–OCD combined psychopathology is more akin to SCH than to OCD.

Tension Pyopneumothorax due to a Ruptured Pulmonary Echinococcal Cyst

cin as well as 6 months of daily albendazole 400 mg b.i.d. for the first 3 weeks of every month. A week later he was readmitted due to recurrent syncope and hypotension. He had an elevated JVP and no breath sounds on the right side. There was also marked new eosinophilia. CT demonstrated a new massive right pleural effusion compressing the superior vena cava and right heart and necessitating emergency drainage of what was an overt empyema with a pH of 6.8 ( fig. 2 a). During hospitalization he reA 38-year-old otherwise healthy man presented to the emergency department with a 3-day history of fever, dyspnea, pleuritic chest pain, and hemoptysis. CT scan suggested a hydatid lung cyst ( fig. 1 ) without evidence of other organ involvement. Sputum microscopy revealed echinococcal protoscolices of various maturations, and sputum cultures yielded Acinetobacter baumanii. The patient refused surgery and was discharged for medical therapy with 2 weeks of oral clindamycin and levofloxaPublished online: August 4, 2012