The prefrontal-limbic network in depression: A core pathology of synapse regression

Grey matter loss occurs in different components of the prefrontal-limbic network (PLN) implicated in major depressive disorder (MDD). This must be accounted for by specific pathologies of cells and their processes that comprise the grey matter. In order to identify these a quantitative evaluation of the contributions of neurons, glial cells, blood vessels and extracellular space to the grey matter volume is determined. This forms the basis of evaluating the various claims that the core pathology of certain cell types and/or their processes are responsible for the grey matter loss. It is concluded that it is the loss of synapses and concomitantly that of the dendrites on which they normally impinge that accounts quantitatively for the major loss of grey matter in different components of the PLN in depression.     

Mind does really matter: evidence from neuroimaging studies of emotional self-regulation, psychotherapy, and placebo effect

This article reviews neuroimaging studies of conscious and voluntary regulation of various emotional states (sexual arousal, sadness, negative emotion). The results of these studies show that metacognition and cognitive recontextualization selectively alters the way the brain processes and reacts to emotional stimuli. Neuroimaging studies of the effect of psychotherapy in patients suffering from diverse forms of psychopathology (obsessive-compulsive disorder, panic disorder, unipolar major depressive disorder, social phobia, spider phobia, borderline personality) are also examined. The results of these studies indicate that the mental functions and processes involved in diverse forms of psychotherapy exert a significant influence on brain activity. Neuroimaging investigations of the placebo effect in healthy individuals (placebo analgesia, psychostimulant expectation) and patients with Parkinson's disease or unipolar major depressive disorder are also reviewed. The results of these investigations demonstrate that beliefs and expectations can markedly modulate neurophysiological and neurochemical activity in brain regions involved in perception, movement, pain, and various aspects of emotion processing. Collectively, the findings of the neuroimaging studies reviewed here strongly support the view that the subjective nature and the intentional content (what they are "about" from a first-person perspective) of mental processes (e.g., thoughts, feelings, beliefs, volition) significantly influence the various levels of brain functioning (e.g., molecular, cellular, neural circuit) and brain plasticity. Furthermore, these findings indicate that mentalistic variables have to be seriously taken into account to reach a correct understanding of the neural bases of behavior in humans. An attempt is made to interpret the results of these neuroimaging studies with a new theoretical framework called the Psychoneural Translation Hypothesis.     

Cholinergic modulation of cognition: insights from human pharmacological functional neuroimaging

Evidence from lesion and cortical-slice studies implicate the neocortical cholinergic system in the modulation of sensory, attentional and memory processing. In this review we consider findings from sixty-three healthy human cholinergic functional neuroimaging studies that probe interactions of cholinergic drugs with brain activation profiles, and relate these to contemporary neurobiological models. Consistent patterns that emerge are: (1) the direction of cholinergic modulation of sensory cortex activations depends upon top-down influences; (2) cholinergic hyperstimulation reduces top-down selective modulation of sensory cortices; (3) cholinergic hyperstimulation interacts with task-specific frontoparietal activations according to one of several patterns, including: suppression of parietal-mediated reorienting; decreasing 'effort'-associated activations in prefrontal regions; and deactivation of a 'resting-state network' in medial cortex, with reciprocal recruitment of dorsolateral frontoparietal regions during performance-challenging conditions; (4) encoding-related activations in both neocortical and hippocampal regions are disrupted by cholinergic blockade, or enhanced with cholinergic stimulation, while the opposite profile is observed during retrieval; (5) many examples exist of an 'inverted-U shaped' pattern of cholinergic influences by which the direction of functional neural activation (and performance) depends upon both task (e.g. relative difficulty) and subject (e.g. age) factors. Overall, human cholinergic functional neuroimaging studies both corroborate and extend physiological accounts of cholinergic function arising from other experimental contexts, while providing mechanistic insights into cholinergic-acting drugs and their potential clinical applications.     

Toward a neurobiology of delusions

Delusions are the false and often incorrigible beliefs that can cause severe suffering in mental illness. We cannot yet explain them in terms of underlying neurobiological abnormalities. However, by drawing on recent advances in the biological, computational and psychological processes of reinforcement learning, memory, and perception it may be feasible to account for delusions in terms of cognition and brain function. The account focuses on a particular parameter, prediction error – the mismatch between expectation and experience – that provides a computational mechanism common to cortical hierarchies, fronto-striatal circuits and the amygdala as well as parietal cortices. We suggest that delusions result from aberrations in how brain circuits specify hierarchical predictions, and how they compute and respond to prediction errors. Defects in these fundamental brain mechanisms can vitiate perception, memory, bodily agency and social learning such that individuals with delusions experience an internal and external world that healthy individuals would find difficult to comprehend. The present model attempts to provide a framework through which we can build a mechanistic and translational understanding of these puzzling symptoms.     

Biomarkers for major depression and its delineation from neurodegenerative disorders

Major depressive disorders (MDD) are among the most debilitating diseases worldwide and occur with a high prevalence in elderly individuals. Neurodegenerative diseases (in particular Alzheimer's disease, AD) do also show a strong age-dependent increase in incidence and prevalence among the elderly population. A high number of geriatric patients with MDD show cognitive deficits and a very high proportion of AD patients present co-morbid MDD, which poses difficult diagnostic and prognostic questions. Especially in prodromal and in very early stages of AD, it is almost impossible to differentiate between pure MDD and MDD with underlying AD. Here, we give a comprehensive review of the literature on the current state of candidate biomarkers for MDD ("positive MDD markers") and briefly refer to established and validated diagnostic AD biomarkers in order to rule out underlying AD pathophysiology in elderly MDD subjects with cognitive impairments ("negative MDD biomarkers"). In summary, to date there is no evidence for positive diagnostic MDD biomarkers and the only way to delineate MDD from AD is to use "negative MDD" biomarkers. Because of this highly unsatisfactory current state of MDD biomarker research, we propose a research strategy targeting to detect and validate positive MDD biomarkers, which is based on a complex (genetic, molecular and neurophysiological) biological model that incorporates current state of the art knowledge on the pathobiology of MDD. This model delineates common pathways and the intersection between AD and MDD. Applying these concepts to MDD gives hope that positive MDD biomarkers can be successfully identified in the near future.     

Multimodal transcranial magnetic stimulation: using concurrent neuroimaging to reveal the neural network dynamics of noninvasive brain stimulation

Since its introduction in the 1980s, Transcranial Magnetic Stimulation (TMS) has proven to be a versatile method to non-invasively study human brain function by reversibly altering ongoing neural processing. In addition, TMS has been explored as a therapeutic intervention in a number of neurological and neuropsychiatric conditions. However, our understanding of TMS-induced changes in neural activity patterns is still rather limited, particularly when it comes to changes in neural network dynamics beyond the cortical site directly targeted by TMS. In order to monitor both its local and remote neurophysiological effects, TMS has been combined with complementary neuroimaging methods that allow additional insights into how observed TMS effects at the behavioral level can be interpreted by taking into account the full scale of its impact throughout the brain. The current review provides a comprehensive overview of the existing multimodal TMS literature, covering studies in which TMS was combined with one of the three main neuroimaging modalities, namely Electroencephalography, Positron Emission Tomography, and functional Magnetic Resonance Imaging. Besides constituting a reflection of the status quo in this exciting multidisciplinary research field, this review additionally reveals both convergent and divergent observations across modalities that await corroboration or resolution, thereby further guiding ongoing basic research and providing useful constraints to optimize future clinical applications.     

Overlapping prefrontal systems involved in cognitive and emotional processing in euthymic bipolar disorder and following sleep deprivation: A review of functional neuroimaging studies

Prefrontal cortex (PFC) mediated cognitive and emotional processing deficits in bipolar disorder lead to functional limitations even during periods of mood stability. Alterations of sleep and circadian functioning are well-documented in bipolar disorder, but there is little research directly examining the mechanistic role of sleep and/or circadian rhythms in the observed cognitive and emotional processing deficits. We systematically review the cognitive and emotional processing deficits reliant upon PFC functioning of euthymic patients with bipolar disorder and in healthy individuals deprived of sleep. The evidence from two parallel lines of investigation suggests that sleep and circadian rhythms may be involved in the cognitive and emotional processing deficits seen in bipolar disorder through overlapping neurobiological systems. We discuss current models of bipolar highlighting the PFC-limbic connections and discuss inclusion of sleep-related mechanisms. Sleep and circadian dysfunction is a core feature of bipolar disorder and models of neurobiological abnormalities should incorporate chronobiological measures. Further research into the role of sleep and circadian rhythms in cognition and emotional processing in bipolar disorder is warranted.     

The brain and its resting state activity--experimental and methodological implications

Despite all the recent progress in neuroscience, we still do not understand the basic principles according to which the brain functions. This may be due, at least in part, to our lack of knowledge how the brain's intrinsic activity, the brain's input, impacts stimulus-induced changes in the brain. We here discuss the neuronal, experimental and methodological relevance of the brain's resting state activity for future studies. Furthermore, we make several suggestions how to best define and include the brain's resting state into our experimental designs. We conclude that experimental consideration of the brain's resting state has major implications for setting up experimental designs and methodological strategies. This may also shed new light on some hitherto unresolved questions like the neuroscientific mechanisms underlying consciousness and psychiatric disorders.     

The effects of morphine on basal neuronal activities in the lateral and medial pain pathways

Numerous studies indicate that morphine suppresses pain-evoked activities in both spinal and supraspinal regions. However, little is known about the effect of morphine on the basal brain activity in the absence of pain. The present study was designed to assess the effects of single-dose morphine on the spontaneous discharge of many simultaneously recorded single units, as well as their functional connections, in the lateral pain pathway, including the primary somatosensory cortex (SI) and ventral posterolateral thalamus (VPL), and medial pain pathway, including the anterior cingulate cortex (ACC) and medial dorsal thalamus (MD), in awake rats. Morphine (5 mg/kg) was administered intraperitoneally before the recording. Naloxone plus morphine and normal saline injections were performed respectively as controls. The results showed that morphine administration produced significant changes in the spontaneous neuronal activity in more than one third of the total recorded neurons, with primary activation in the lateral pathway while both inhibition and activation in the medial pathway. Naloxone pretreatment completely blocked the effects induced by morphine. In addition, the correlated activities between and within both pain pathways was exclusively suppressed after morphine injection. These results suggest that morphine may play different roles in modulating neural activity in normal vs. pain states. Taken together, this is the first study investigating the morphine modulation of spontaneous neuronal activity within parallel pain pathways. It can be helpful for revealing neuronal population coding for the morphine action in the absence of pain, and shed light on the supraspinal mechanisms for preemptive analgesia.     

Hyperbaric oxygen therapy might improve certain pathophysiological findings in autism

Autism is a neurodevelopmental disorder currently affecting as many as 1 out of 166 children in the United States. Numerous studies of autistic individuals have revealed evidence of cerebral hypoperfusion, neuroinflammation and gastrointestinal inflammation, immune dysregulation, oxidative stress, relative mitochondrial dysfunction, neurotransmitter abnormalities, impaired detoxification of toxins, dysbiosis, and impaired production of porphyrins. Many of these findings have been correlated with core autistic symptoms. For example, cerebral hypoperfusion in autistic children has been correlated with repetitive, self-stimulatory and stereotypical behaviors, and impairments in communication, sensory perception, and social interaction. Hyperbaric oxygen therapy (HBOT) might be able to improve each of these problems in autistic individuals. Specifically, HBOT has been used with clinical success in several cerebral hypoperfusion conditions and can compensate for decreased blood flow by increasing the oxygen content of plasma and body tissues. HBOT has been reported to possess strong anti-inflammatory properties and has been shown to improve immune function. There is evidence that oxidative stress can be reduced with HBOT through the upregulation of antioxidant enzymes. HBOT can also increase the function and production of mitochondria and improve neurotransmitter abnormalities. In addition, HBOT upregulates enzymes that can help with detoxification problems specifically found in autistic children. Dysbiosis is common in autistic children and HBOT can improve this. Impaired production of porphyrins in autistic children might affect the production of heme, and HBOT might help overcome the effects of this problem. Finally, HBOT has been shown to mobilize stem cells from the bone marrow to the systemic circulation. Recent studies in humans have shown that stem cells can enter the brain and form new neurons, astrocytes, and microglia. It is expected that amelioration of these underlying pathophysiological problems through the use of HBOT will lead to improvements in autistic symptoms. Several studies on the use of HBOT in autistic children are currently underway and early results are promising.     

The pain matrix reloaded: a salience detection system for the body

Neuroimaging and neurophysiological studies have shown that nociceptive stimuli elicit responses in an extensive cortical network including somatosensory, insular and cingulate areas, as well as frontal and parietal areas. This network, often referred to as the "pain matrix", is viewed as representing the activity by which the intensity and unpleasantness of the perception elicited by a nociceptive stimulus are represented. However, recent experiments have reported (i) that pain intensity can be dissociated from the magnitude of responses in the "pain matrix", (ii) that the responses in the "pain matrix" are strongly influenced by the context within which the nociceptive stimuli appear, and (iii) that non-nociceptive stimuli can elicit cortical responses with a spatial configuration similar to that of the "pain matrix". For these reasons, we propose an alternative view of the functional significance of this cortical network, in which it reflects a system involved in detecting, orienting attention towards, and reacting to the occurrence of salient sensory events. This cortical network might represent a basic mechanism through which significant events for the body's integrity are detected, regardless of the sensory channel through which these events are conveyed. This function would involve the construction of a multimodal cortical representation of the body and nearby space. Under the assumption that this network acts as a defensive system signaling potentially damaging threats for the body, emphasis is no longer on the quality of the sensation elicited by noxious stimuli but on the action prompted by the occurrence of potential threats.     

Reliability and precision of pseudo‐continuous arterial spin labeling perfusion MRI on 3.0 T and comparison with 15O‐water PET in elderly subjects at risk for Alzheimer's disease

Arterial spin labeling (ASL) offers MRI measurement of cerebral blood flow (CBF) in vivo, and may offer clinical diagnostic utility in populations such as those with early Alzheimer's disease (AD). In the current study, we investigated the reliability and precision of a pseudo‐continuous ASL (pcASL) sequence that was performed two or three times within one hour on eight young normal control subjects, and 14 elderly subjects including 11 with normal cognition, one with AD and two with Mild Cognitive Impairment (MCI). Six of these elderly subjects including one AD, two MCIs and three controls also received ¹⁵O‐water positron emission tomography (PET) scans 2 h before their pcASL MR scan. The instrumental reliability of pcASL was evaluated with the intraclass correlation coefficient (ICC). The ICCs were greater than 0.90 in pcASL global perfusion measurements for both the young and the elderly groups. The cross‐modality perfusion imaging comparison yielded very good global and regional agreement in global gray matter and the posterior cingulate cortex. Significant negative correlation was found between age and the gray/white matter perfusion ratio (r = –0.62, p < 0.002). The AD and MCI patients showed the lowest gray/white matter perfusion ratio among all the subjects. The data suggest that pcASL provides a reliable whole brain CBF measurement in young and elderly adults whose results converge with those obtained with the traditional ¹⁵O‐water PET perfusion imaging method. pcASL perfusion MRI offers an alternative method for non‐invasive in vivo examination of early pathophysiological changes in AD. Copyright © 2009 John Wiley & Sons, Ltd.     

Language and cortical function: conceptual developments

Mastery of a language is a capacity that distinguishes humans from other animals. Attempts to identify the brain functions that are necessary for the possession of linguistic skills began in the 19th century with the research of Broca and Wernicke. We trace the principal experimental developments since then, ranging from psychological studies of aphasic patients to non-invasive brain-imaging investigations. The development of theories concerning word recognition, reading aloud, fluent speech and understanding utterances are described. Possible brain regions involved in these abilities, identified by means of non-invasive imaging, are considered. We examine the various claims made by these researchers as to what their experiments show and in particular examine the validity of their theories. This conceptual analysis shows that in many cases the interpretation of experiments is confused and that the theories elaborated are not tenable. We seek to clarify what can be substantiated concerning the workings of the brain and the exercise of linguistic skills.     

The effects of paraquat on regional brain neurotransmitter activity, hippocampal BDNF and behavioural function in female mice

Accumulating evidence implicates pesticides such as paraquat in the development of Parkinson's disease (PD). Indeed, paraquat exposure is associated with an increased risk of PD and when administered to rodents the pesticide recapitulates many of the neuropathological and behavioural features of the disease. However, it is unclear whether any sexual dimorphism exists in the in vivo murine response to paraquat intoxication, since most studies have used exclusively males. Accordingly, we sought to determine the impact of repeated paraquat exposure on a range of neural and behavioural outcomes in female C57BL/6J mice. The present investigation revealed that the female mice were largely resistant to the paraquat-induced nigrostriatal dopamine changes and locomotor deficits that were reported previously in males. Similarly, in contrast to the reductions of hippocamapal brain-derived neurotrophic factor (BDNF) previously reported in paraquat treated male mice, the herbicide actually increased levels of the trophic factor in females. Yet, similar to our previous findings in males, paraquat increased norepinephrine utilization within the hippocampus and prefrontal cortex of the female mice. However, these changes did not translate into anxiety- or- depression-like behaviours in the open field test, as the females actually seemed to show enhanced exploration. Consistent with reports of a greater incidence of PD in males, these data suggest that female mice may be less susceptible than males to the nigrostriatal dopaminergic and motor effects of environmental toxins. The augmented hippocampal BDNF and noradrenergic changes observed could conceivably act to buffer female mice against some of the deleterious behavioural effects of parquat.     

Multidisciplinary perspectives on attention and the development of self-regulation

During infancy and early childhood, children develop their ability to regulate their own emotions and behavior. This development of self-regulatory mechanisms has been considered to be the crucial link between genetic predisposition, early experience, and later adult functioning in society. This paper brings together the updated empirical findings related to the role of attention and the maturation of brain frontal areas in self-regulation. It reviews viewpoints and evidence of disciplines such as developmental psychology, cognitive neuroscience, social psychology, and neurobiology. It examines the causes of individual differences in self-regulation and the effects of those differences on the social and academic functioning of the individual. The consequences of failure in self-regulation are illustrated by focusing on the attention deficit/hyperactivity disorder (ADHD), including a detailed review of the animal models related to this disorder. Finally, some initial evidence suggesting the possibility of fostering self-regulation through training of attention is presented.     

Seeing the invisible: the scope and limits of unconscious processing in binocular rivalry

When an image is presented to one eye and a very different image is presented to the corresponding location of the other eye, the two images compete for conscious representations, such that only one image is visible at a time while the other is suppressed. Called binocular rivalry, this phenomenon and its deviants have been extensively exploited to study the mechanism and neural correlates of consciousness. In this paper, we propose a framework - the unconscious binding hypothesis - to distinguish unconscious processing from conscious processing. According to this framework, the unconscious mind not only encodes individual features but also temporally binds distributed features to give rise to cortical representations; unlike conscious binding, however, unconscious binding is fragile. Under this framework, we review evidence from psychophysical and neuroimaging studies and come to two important conclusions. First, processing of invisible features depends on the "level" of the features as defined by their neural mechanisms. For low-level simple features, prolonged exposure to visual patterns (e.g. tilt) and simple translational motion can alter the appearance of subsequent visible features (i.e. adaptation). For invisible high-level features, complex spiral motion cannot produce adaptation, nor can objects/words enhance subsequent processing of related stimuli (i.e. priming). Yet images of tools can activate the dorsal pathway. Second, processing of invisible features has functional significance. Although invisible central cues cannot orient attention, invisible erotic pictures in the periphery can nevertheless guide attention, likely through emotional arousal; reciprocally, the processing of invisible information can be modulated by attention.     

The cognitive functions of the caudate nucleus

The basal ganglia as a whole are broadly responsible for sensorimotor coordination, including response selection and initiation. However, it has become increasingly clear that regions of the basal ganglia are functionally delineated along corticostriatal lines, and that a modular conception of the respective functions of various nuclei is useful. Here we examine the specific role of the caudate nucleus, and in particular, how this differs from that of the putamen. This review considers converging evidence from multiple domains including anatomical studies of corticostriatal circuitry, neuroimaging studies of healthy volunteers, patient studies of performance deficits on a variety of cognitive tests, and animal studies of behavioural control. We conclude that the caudate nucleus contributes to behaviour through the excitation of correct action schemas and the selection of appropriate sub-goals based on an evaluation of action-outcomes; both processes fundamental to successful goal-directed action. This is in contrast to the putamen, which appears to subserve cognitive functions more limited to stimulus-response, or habit, learning. This modular conception of the striatum is consistent with hierarchical models of cortico-striatal function through which adaptive behaviour towards significant goals can be identified (motivation; ventral striatum), planned (cognition; caudate) and implemented (sensorimotor coordination; putamen) effectively.     

Fundamental mechanisms of visual motion detection: models,cells and functions

Taking a comparative approach, data from a range of visual species are discussed in the context of ideas about mechanisms of motion detection. The cellular basis of motion detection in the vertebrate retina, sub-cortical structures and visual cortex is reviewed alongside that of the insect optic lobes. Special care is taken to relate concepts from theoretical models to the neural circuitry in biological systems. Motion detection involves spatiotemporal pre-filters, temporal delay filters and non-linear interactions. A number of different types of non-linear mechanism such as facilitation, inhibition and division have been proposed to underlie direction selectivity. The resulting direction-selective mechanisms can be combined to produce speed-tuned motion detectors. Motion detection is a dynamic process with adaptation as a fundamental property. The behavior of adaptive mechanisms in motion detection is discussed, focusing on the informational basis of motion adaptation, its phenomenology in human vision, and its cellular basis. The question of whether motion adaptation serves a function or is simply the result of neural fatigue is critically addressed.     

Brain imaging correlates of verbal working memory in children following traumatic brain injury

Neural correlates of working memory (WM) based on the Sternberg Item Recognition Task (SIRT) were assessed in 40 children with moderate-to-severe traumatic brain injury (TBI) compared to 41 demographically-comparable children with orthopedic injury (OI). Multiple magnetic resonance imaging (MRI) methods assessed structural and functional brain correlates of WM, including volumetric and cortical thickness measures on all children; functional MRI (fMRI) and diffusion tensor imaging (DTI) were performed on a subset of children. Confirming previous findings, children with TBI had decreased cortical thickness and volume as compared to the OI group. Although the findings did not confirm the predicted relation of decreased frontal lobe cortical thickness and volume to SIRT performance, left parietal volume was negatively related to reaction time (RT). In contrast, cortical thickness was positively related to SIRT accuracy and RT in the OI group, particularly in aspects of the frontal and parietal lobes, but these relationships were less robust in the TBI group. We attribute these findings to disrupted fronto-parietal functioning in attention and WM. fMRI results from a subsample demonstrated fronto-temporal activation in the OI group, and parietal activation in the TBI group, and DTI findings reflected multiple differences in white matter tracts that engage fronto-parietal networks. Diminished white matter integrity of the frontal lobes and cingulum bundle as measured by DTI was associated with longer RT on the SIRT. Across modalities, the cingulate emerged as a common structure related to performance after TBI. These results are discussed in terms of how different imaging modalities tap different types of pathologic correlates of brain injury and their relationship with WM.     

The serotonergic system in ageing and Alzheimer's disease

Alzheimer's disease (AD) is one of the major neurodegenerative diseases that deteriorates cognitive functions and primarily affects associated brain regions involved in learning and memory, such as the neocortex and the hippocampus. Following the discovery and establishment of its role as a neurotransmitter, serotonin (5-HT), was found to be involved in a multitude of neurophysiological processes including mnesic function, through its dedicated pathways and interaction with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. Abnormal 5-HT neurotransmission contributes to the deterioration of cognitive processes in ageing, AD and other neuropathologies, including schizophrenia, stress, mood disorders and depression. Numerous studies have confirmed the pathophysiological role of the 5-HT system in AD and that several drugs enhancing 5-HT neurotransmission are effective in treating the AD-related cognitive and behavioural deficits. Here we present a comprehensive overview of the role of serotonergic neurotransmission in brain development, maturation and ageing, discuss its role in higher brain function and provide an in depth account of pathological modifications of serotonergic transmission in neurological diseases and AD.