Substantia nigra/ventral tegmental reward prediction error disruption in psychosis

While dopamine systems have been implicated in the pathophysiology of schizophrenia and psychosis for many years, how dopamine dysfunction generates psychotic symptoms remains unknown. Recent theoretical interest has been directed at relating the known role of midbrain dopamine neurons in reinforcement learning, motivational salience and prediction error to explain the abnormal mental experience of psychosis. However, this theoretical model has yet to be explored empirically. To examine a link between psychotic experience, reward learning and dysfunction of the dopaminergic midbrain and associated target regions, we asked a group of first episode psychosis patients suffering from active positive symptoms and a group of healthy control participants to perform an instrumental reward conditioning experiment. We characterized neural responses using functional magnetic resonance imaging. We observed that patients with psychosis exhibit abnormal physiological responses associated with reward prediction error in the dopaminergic midbrain, striatum and limbic system, and we demonstrated subtle abnormalities in the ability of psychosis patients to discriminate between motivationally salient and neutral stimuli. This study provides the first evidence linking abnormal mesolimbic activity, reward learning and psychosis.     

Preclinical and clinical neural network changes in SCA2 parkinsonism

BackgroundThe pathophysiological changes before the presentation of clinical symptoms in parkinsonism are unclear. In this study, we investigated neural network modulations in persons in the preclinical stage of familial parkinsonism, and how the network interactions change at the clinical stage.MethodsWe performed functional MRI in a family with SCA2 mutation, including 9 asymptomatic carriers and 10 mutation carriers with parkinsonian symptoms. Functional connectivity from the posterior putamen bilaterally and rostral supplementary motor area was used to explore network interactions in the subjects.ResultsBoth the asymptomatic carriers and patients had decreased connectivity within the basal ganglia-thalamus-cortical motor loop compared to controls. The asymptomatic carriers showed extensively increased connectivity compared to controls, including the cortico-cortical motor, cortico-cerebellar, cortico-brainstem, and part of the basal ganglia-thalamus-cortical motor circuits. In contrast, the connectivity of most of these networks was decreased in the patients. These abnormalities were relatively normalized after levodopa administration.ConclusionsIn the preclinical stage of SCA2 parkinsonism, the connectivity of a part of the basal ganglia motor loop is weakened as a consequence of dopaminergic deficits; meanwhile, the connectivity of other large-scale brain networks is strengthened presumably to compensate for the dysfunction of the basal ganglia to maintain brain function in the early stage of dopaminergic deficits. The simultaneous effects of progressive disruption of basal ganglia motor circuits and failure of compensatory mechanisms as dopaminergic dysfunction progresses may contribute to the onset of clinical symptoms.     

An MRI study of midbrain morphology in patients with schizophrenia: relationship to psychosis, neuroleptics, and cerebellar neural circuitry.

BACKGROUND: The midbrain contains the perikarya of all the dopamine neurons in the human brain. Although other neurochemicals may well be involved, dopamine dysregulation is central in the pathophysiology of psychosis. Despite this, few imaging studies have evaluated the morphology of the midbrain. METHODS: Using high-resolution magnetic resonance imaging, morphology of three posterior fossa and brain stem structures were measured: midbrain, pons, and medulla. The patient sample consisted of 50 men with schizophrenia, matched by gender and age to 50 healthy control subjects. RESULTS: Patients had significantly smaller midbrain measures compared with control subjects. There were no differences between groups in measures of pons or medulla. Furthermore, midbrain size was significantly and inversely correlated with positive symptoms and cumulative neuroleptic exposure, but not with negative or disorganized symptoms. After controlling for the effect of cumulative neuroleptic exposure, the relationship between midbrain morphology and positive symptoms remained significant. CONCLUSIONS: Midbrain morphology of patients with schizophrenia is abnormal, being smaller in patients compared with control subjects. Although this appears to be specifically related to psychotic symptoms, there is also a robust medication effect, with greater exposure to neuroleptics being associated with greater morphologic abnormality. We discuss the role of dopaminergic dysregulation and possible neural circuit involvement.     

Molecular brain imaging and the neurobiology and genetics of schizophrenia

It has been hypothesized that schizophrenia is related to dysfunction in temporolimbic-prefrontal neuronal networks, which is acquired early in an individual's development. After puberty, relatively reduced prefrontal control of striatal dopaminergic neurotransmission may lead to unmodulated striatal dopamine (DA) activity, and the positive symptoms of acute psychosis. Brain imaging studies support the notion of prefrontal dysfunction in schizophrenia and correlated upregulation of presynaptic striatal DA activity. Recent molecular brain imaging studies have combined genetic assessments with a multimodal neuroimaging approach to further refine our understanding of the pathophysiologic architecture of the disorder. We review the literature on functional brain imaging in schizophrenia and discuss genotype effects on core psychotic symptoms. A promising research strategy is the identification of genetic and environmental factors that contribute to intermediate phenotypes such as working memory deficits in schizophrenia. Molecular brain imaging can help to unravel the complex interactions between genes and environment and its association with neuronal network dysfunction in schizophrenia.     

Optogenetic approaches to evaluate striatal function in animal models of Parkinson disease

Optogenetics refers to the ability to control cells that have been genetically modified to express light-sensitive ion channels. The introduction of optogenetic approaches has facilitated the dissection of neural circuits. Optogenetics allows for the precise stimulation and inhibition of specific sets of neurons and their projections with fine temporal specificity. These techniques are ideally suited to investigating neural circuitry underlying motor and cognitive dysfunction in animal models of human disease. Here, we focus on how optogenetics has been used over the last decade to probe striatal circuits that are involved in Parkinson disease, a neurodegenerative condition involving motor and cognitive abnormalities resulting from degeneration of midbrain dopaminergic neurons. The precise mechanisms underlying the striatal contribution to both cognitive and motor dysfunction in Parkinson disease are unknown. Although optogenetic approaches are somewhat removed from clinical use, insight from these studies can help identify novel therapeutic targets and may inspire new treatments for Parkinson disease. Elucidating how neuronal and behavioral functions are influenced and potentially rescued by optogenetic manipulation in animal models could prove to be translatable to humans. These insights can be used to guide future brain-stimulation approaches for motor and cognitive abnormalities in Parkinson disease and other neuropsychiatric diseases.     

Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders

Schizophrenia remains a major health burden, highlighting the need for new treatment approaches. We consider the potential for targeting the trace amine (TA) system. We first review genetic, preclinical, and clinical evidence for the role of TAs in the aetiopathology of schizophrenia. We then consider how the localisation and function of the trace amine-associated receptor 1 (TAAR1) position it to modulate key brain circuits for the disorder. Studies in rodents using Taar1 knockout (TAAR1-KO) and overexpression models show that TAAR1 agonism inhibits midbrain dopaminergic and serotonergic activity, and enhances prefrontal glutamatergic function. TAAR1 agonists also reduce hyperactivity, attenuate prepulse inhibition (PPI) deficits and social withdrawal, and improve cognitive measures in animal models. Finally, we consider findings from clinical trials of TAAR1 agonists and how this approach may address psychotic and negative symptoms, tolerability issues, and other unmet needs in the treatment of schizophrenia.     

Emotion circuits differentiate symptoms of psychosis versus mania in adolescents

The diagnostic boundary between schizophrenia and bipolar disorder can be unclear, particularly with early onset. We assessed if emotion brain circuits differentiate psychosis versus mania symptoms in a series of six early onset patients. Symptoms were dissociated by direction, awareness condition, and brain regions. Greater psychosis symptoms were correlated with greater prefrontal, anterior cingulate, amygdala, and fusiform face area activation during masked fear processing. By contrast, greater mania symptoms were correlated with less amygdala activation during unmasked fear and happy processing. This suggests emotion dysfunction in schizophrenia versus bipolar disorder may arise from partially distinct neural mechanisms of susceptibility.     

Mapping preclinical compensation in Parkinson's disease: An imaging genomics approach

Mutations in the Parkin (PARK2) and PINK1 gene (PARK 6) can cause recessively inherited Parkinson's disease (PD). The presence of a single Parkin or PINK1 mutation is associated with a dopaminergic nigrostriatal dysfunction and conveys an increased risk to develop PD throughout lifetime. Therefore neuroimaging of non‐manifesting individuals with a mutant Parkin or PINK1 allele opens up a window for the investigation of preclinical and very early phases of PD in vivo. Here we review how functional magnetic resonance imaging (fMRI) can be used to identify compensatory mechanisms that help to prevent development of overt disease. In two separate experiments, Parkin mutation carriers displayed stronger activation of rostral supplementary motor area (SMA) and right dorsal premotor cortex (PMd) during a simple motor sequence task and anterior cingulate motor area and left rostral PMd during internal movement selection as opposed to externally cued movements. The additional recruitment of the rostral SMA and right rostral PMd during the finger sequence task was also observed in a separate group of nonmanifesting mutation carriers with a single heterozygous PINK1 mutation. Because mutation carriers were not impaired at performing the task, the additional recruitment of motor cortical areas indicates a compensatory mechanism that effectively counteracts the nigrostriatal dysfunction. These first results warrant further studies that use these imaging genomics approach to tap into preclinical compensation of PD. Extensions of this line of research involve fMRI paradigms probing nonmotor brain functions. Additionally, the same fMRI paradigms should be applied to nonmanifesting mutation carriers in genes linked to autosomal dominant PD. This will help to determine how “generically” the human brain compensates for a preclinical dopaminergic dysfunction. © 2009 Movement Disorder Society     

帕金森病的功能磁共振成像研究进展

帕金森病（PD）的主要病理改变是黑质多巴胺能神经元变性坏死并引起多巴胺递质减少,通过神经环路可引起包括脑皮质在内广泛的功能及结构改变.功能磁共振成像（fMRI）作为一项功能影像技术能灵敏地检测出这些变化,进而有可能为PD早期诊断提供依据.本文就PD的fMRI研究进展进行综述.     

Longitudinal Assessment and Functional Neuroimaging of Movement Variability Reveal Novel Insights Into Motor Dysfunction in Clinical High Risk for Psychosis

Motor dysfunction in youth at clinical high risk (CHR) for psychosis is thought to reflect abnormal neurodevelopment within cortical-subcortical motor circuits and may be important for understanding clinical trajectories of CHR individuals. However, to date, our perspective of brain-behavior relationships has been informed solely by cross-sectional correlational studies linking behavior in the lab to brain structure or respective resting-state network connectivity. Here, we assess movement dysfunction from 2 perspectives: study 1 investigates the longitudinal progression of handwriting variability and positive symptoms in a sample of 91 CHR and healthy controls during a 12-month follow-up and study 2 involves a multiband functional magnetic resonance imaging task exploring the relationship between power grip force stability and motor network brain activation in a subset of participants. In study 1, we found that greater handwriting variability was a stable feature of CHR participants who experienced worse symptom progression. Study 2 results showed that CHR individuals had greater variability in their grip force and greater variability was related to decreased activation in the associative cortico-striatal network compared to controls. Motor variability may be a stable marker of vulnerability for psychosis risk and possible indicator of a vulnerable cortico-striatal brain network functioning in CHR participants, although the effects of antipsychotic medication should be considered.     

Pathophysiology of Parkinson's disease

Parkinson's disease (PD) has classically been considered a disease of motor dysfunction, but it also includes psychiatric symptoms. To better understand the symptoms and signs that accompany PD, the interrelationships of deep brain structures and cortical areas involved with this neurodegenerative disease must be investigated.Current models of basal ganglia/cortical physiology attempt to integrate motor and nonmotor physiology and describe the pathophysiology attributable to PD. The cortical areas comprising basal ganglia/cortical loops include frontal structures involved in motor program as well as more prefrontal structures likely subserving non-motor functions such as cognition. The etiology of PD is not clear, but studies have implicated oxidative stress from exogenous stressors or endogenous neurotoxins. A large number of PD patients have been found to exhibit mitochondrial dysfunction. Lewy bodies are seen within dopaminergic and other neuronal populations affected in PD, and they stain positive for ubiquitin and alpha-synuclein. The small percentage of familial PD has often been found to coincide with dominantly inherited mutations in the gene for alpha-synuclein, or with the recessive gene mutation for parkin, which is involved in the ubiquitination pathway. Selected neuronal populations are affected in PD, and the neurodegeneration may include dopaminergic neurons outside the substantia nigra pars compacta, as well and non-dopaminergic neurons. The loss of these neuronal populations within the basal ganglia-frontal circuits can have a profound effect upon the motor and neurobehavioral symptoms in PD. L-dopa remains the most effective pharmacologic therapy for PD, however as the disease progresses, the drug loses its efficacy and troublesome sideeffects often occur. The renewal of surgical interventions for PD has increased the insight into the pathophysiology of PD,and surgical lesions have shown that motor and cognitive fronto-subcortical circuits are seemingly segregated in patients with PD. Investigation into these circuits helps provides models underlying motor and cognitive pathophysiology of PD.     

Neurochemical findings in the MPTP model of Parkinson's disease

Summary. Animal models are a very important approach to study the pathogenesis and therapeutic intervention strategies of human diseases. Since many human disorders do not arise spontaneously in animals, characteristic functional changes have to be mimicked by neurotoxic agents. For instance, the application of the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is able to produce striking similarities to Parkinson's disease (PD) diagnosed in humans. MPTP is thought to selectively damage dopaminergic neurons predominantly those originating in the substantia nigra pars compacta (SNc) which leads to impaired dopaminergic neurotransmission accompanied by a loss of dopaminergic nerve terminals in the striatum. MPTP-induced neurochemical, behavioral, and histopathological alterations replicate very closely the clinical symptoms of PD patients, which will be discussed in this paper and render the MPTP model currently the most favored PD model to study therapeutic intervention strategies in an easy and reliable way in preclinical studies. We and many other research groups propose that the knowledge about the neurotoxic mechanisms of MPTP such as mitochondrial dysfunction with breakdown of energy metabolism and free radical production will help us to understand the underlying mechanisms of PD, which are not fully understood yet. In particular, the novel aspects of inflammatory processes and the involvement of reactive nitrogen species in addition to reactive oxygen species seem to be important milestones for a better understanding of the neurodegenerative effects of MPTP. In this review we focus on the MPTP mouse model which is easy practicable and widely used in neuroscience research and draw comparisons to the human pathology in PD. Received March 1, 2001; accepted July 11, 2001     

Development, disease and degeneration in schizophrenia: a unitary pathophysiological model

In recent years, several pathophysiological models of schizophrenia, i.e. the early and late brain neurodevelopmental and post-illness onset neurodegenerative models, have been proposed and theorists have often argued as if these explanations are mutually exclusive. We propose that all these mechanisms may interact cumulatively during successive critical ‘windows of vulnerability’ during brain development and during the early course of the illness to lead to the clinical manifestations of the illness. Early brain insults may lead to dysplasia of selective neural networks that account for the premorbid cognitive and psychosocial dysfunction seen in many patients. The onset of psychosis in adolescence may be related to an excessive elimination of synapses and secondarily, phasic dopaminergic overactivity. Following illness onset, these neurochemical alterations in relation to continuing untreated psychosis may lead to further neurodegenerative processes. A reduction in tonic glutamatergic neurotransmission and a phasic glutamatergic excess can potentially predispose to these processes and may have considerable explanatory power. This hypothesis is consistent with central characteristics of schizophrenia such as premorbid manifestations, adolescent onset, functional decline early in this illness, cognitive impairments, the role of dopamine and the role of genes and environment in pathophysiology. This ‘three hit’ model extends similar integrative conceptualization by other investigators and generates testable predictions of relevance to future pathophysiology and treatment research in schizophrenia.     

GABAergic dysfunction in mood disorders

The authors review the available literature on the preclinical and clinical studies involving GABAergic neurotransmission in mood disorders. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter present almost exclusively in the central nervous system (CNS), distributed across almost all brain regions, and expressed in interneurons modulating local circuits. The role of GABAergic dysfunction in mood disorders was first proposed 20 years ago. Preclinical studies have suggested that GABA levels may be decreased in animal models of depression, and clinical studies reported low plasma and CSF GABA levels in mood disorder patients. Also, antidepressants, mood stabilizers, electroconvulsive therapy, and GABA agonists have been shown to reverse the depression-like behavior in animal models and to be effective in unipolar and bipolar patients by increasing brain GABAergic activity. The hypothesis of reduced GABAergic activity in mood disorders may complement the monoaminergic and serotonergic theories, proposing that the balance between multiple neurotransmitter systems may be altered in these disorders. However, low GABAergic cortical function may probably be a feature of a subset of mood disorder patients, representing a genetic susceptibility. In this paper, we discuss the status of GABAergic hypothesis of mood disorders and suggest possible directions for future preclinical and clinical research in this area.     

Threat of punishment motivates memory encoding via amygdala, not midbrain, interactions with the medial temporal lobe

Neural circuits associated with motivated declarative encoding and active threat avoidance have both been described, but the relative contribution of these systems to punishment-motivated encoding remains unknown. The current study used functional magnetic resonance imaging in humans to examine mechanisms of declarative memory enhancement when subjects were motivated to avoid punishments that were contingent on forgetting. A motivational cue on each trial informed participants whether they would be punished or not for forgetting an upcoming scene image. Items associated with the threat of shock were better recognized 24 h later. Punishment-motivated enhancements in subsequent memory were associated with anticipatory activation of right amygdala and increases in its functional connectivity with parahippocampal and orbitofrontal cortices. On a trial-by-trial basis, right amygdala activation during the motivational cue predicted hippocampal activation during encoding of the subsequent scene; across participants, the strength of this interaction predicted memory advantages due to motivation. Of note, punishment-motivated learning was not associated with activation of dopaminergic midbrain, as would be predicted by valence-independent models of motivation to learn. These data are consistent with the view that motivation by punishment activates the amygdala, which in turn prepares the medial temporal lobe for memory formation. The findings further suggest a brain system for declarative learning motivated by punishment that is distinct from that for learning motivated by reward.     

Functional neuroimaging studies in restless legs syndrome

Functional neuroimaging studies may contribute to elucidate pathophysiological mechanisms of the restless legs syndrome (RLS) which still remain unclear. Studies in patients with RLS have been performed using functional magnetic resonance imaging (fMRI), single photon emission computed tomography (SPECT) and, more recently, positron emission tomography (PET). SPECT and PET studies revealed some controversial results of the pre- and postsynaptic dopaminergic neurotransmission system and cerebral metabolism in RLS probably reflecting a dysfunction of the central dopaminergic system. However, it still has to be determined whether these alterations affect the nigrostriatal and/or other central dopaminergic systems like the diencephalospinal or mesolimbic pathway and whether they are the primary mechanisms or only secondary phenomena within the manifestation of RLS symptoms. A subtle receptor dysfunction or a synaptic dopaminergic deficit may play a major role. fMRI investigations of RLS patients revealed an activation in the red nuclei and brainstem close to the reticular formation during the symptomatic period, suggesting that subcortical cerebral generators are involved in the pathogenesis of RLS. However, both techniques are not yet clinically relevant methods to differentiate RLS from other movement disorders during sleep. Further investigations, especially at night when RLS symptoms are most pronounced, will lead to a better understanding of the mechanisms underlying RLS.     

Animal models of the non-motor features of Parkinson's disease

The non-motor symptoms (NMS) of Parkinson's disease (PD) occur in roughly 90% of patients, have a profound negative impact on their quality of life, and often go undiagnosed. NMS typically involve many functional systems, and include sleep disturbances, neuropsychiatric and cognitive deficits, and autonomic and sensory dysfunction. The development and use of animal models have provided valuable insight into the classical motor symptoms of PD over the past few decades. Toxin-induced models provide a suitable approach to study aspects of the disease that derive from the loss of nigrostriatal dopaminergic neurons, a cardinal feature of PD. This also includes some NMS, primarily cognitive dysfunction. However, several NMS poorly respond to dopaminergic treatments, suggesting that they may be due to other pathologies. Recently developed genetic models of PD are providing new ways to model these NMS and identify their mechanisms. This review summarizes the current available literature on the ability of both toxin-induced and genetically-based animal models to reproduce the NMS of PD.