Current pathophysiological theories of schizophrenia highlight the role of altered brain connectivity. This dysconnectivity could manifest 1) anatomically, through structural changes of association fibers at the cellular level, and/or 2) functionally, through aberrant control of synaptic plasticity at the synaptic level. In this article, we review the evidence for these theories, focusing on the modulation of synaptic plasticity. In particular, we discuss how dysconnectivity, observed between brain regions in schizophrenic patients, could result from abnormal modulation of N-methyl-D-aspartate (NMDA)-dependent plasticity by other neurotransmitter systems. We focus on the implication of the dysconnection hypothesis for functional imaging at the systems level. In particular, we review recent advances in measuring plasticity in the human brain using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) that can be used to address dysconnectivity in schizophrenia. Promising experimental paradigms include perceptual and reinforcement learning. We describe how theoretical and causal models of brain responses might contribute to a mechanistic understanding of synaptic plasticity in schizophrenia.
Inferences about brain function, using functional neuroimaging data, require models of how the data were caused. A variety of models are used in practice that range from conceptual models of functional anatomy to nonlinear mathematical models of hemodynamic responses (e.g. as measured by functional magnetic resonance imaging, fMRI) and neuronal responses. In this review, we discuss the most important models used to analyse functional imaging data and demonstrate how they are interrelated. Initially, we briefly review the anatomical foundations of current theories of brain function on which all mathematical models rest. We then introduce some basic statistical models (e.g. the general linear model) used for making classical (i.e. frequentist) and Bayesian inferences about where neuronal responses are expressed. The more challenging question, how these responses are caused, is addressed by models that incorporate biophysical constraints (e.g. forward models from the neural to the hemodynamic level) and/or consider causal interactions between several regions, i.e. models of effective connectivity. Some of the most refined models to date are neuronal mass models of electroencephalographic (EEG) responses. These models enable mechanistic inferences about how evoked responses are caused, at the level of neuronal subpopulations and the coupling among them.
The ability to remember emotional events is crucial for adapting to biologically and socially significant situations. Little is known, however, about the nature of the neural interactions supporting the integration of mnemonic and emotional information. Using fMRI and dynamic models of effective connectivity, we examined regional neural activity and specific interactions between brain regions during a contextual memory retrieval task. We independently manipulated emotional context and relevance of retrieved emotional information to task demands. We show that retrieval of emotionally valenced contextual information is associated with enhanced connectivity from hippocampus to amygdala, structures crucially involved with encoding of emotional events. When retrieval of emotional information is relevant to current behavior, amygdala-hippocampal connectivity increases bidirectionally, under modulatory influences from orbitofrontal cortex, a region implicated in representation of affective value and behavioral guidance. Our findings demonstrate that both memory content and behavioral context impact upon large scale neuronal dynamics underlying emotional retrieval.
Traditionally the posterior parietal cortex was believed to be a sensory structure. More recently, however, its important role in sensory-motor integration has been recognized. One of its functions suggested in this context is the forming of intentions, i.e. high-level cognitive plans for movements. The selection and planning of a specific movement defines motor intention. In this study we used rapid event-related functional magnetic resonance imaging of healthy human subjects to investigate the involvement of posterior parietal cortex in motor intention in response to valid imperative cues. Subjects were provided with either neutral, motor or spatial cues. Neutral cues simply alerted, motor cues indicated which hand to use for response, and spatial cues indicated on which side the target would appear. Importantly, identical targets and responses followed these cues. Therefore any differential neural effects observed are independent from the actual movement performed. Differential blood oxygen level dependent signal changes for motor vs. neutral as well as motor vs. spatial cue trials were found in the left supramarginal gyrus, as hypothesized. The results demonstrate that neural activity in the left supramarginal gyrus underlies motor plans independent from the execution of the movement and thus extend previous neuropsychological and functional imaging data on the role of the left supramarginal gyrus in higher motor cognition.
In fear extinction, an animal learns that a conditioned stimulus (CS) no longer predicts a noxious stimulus [unconditioned stimulus (UCS)] to which it had previously been associated, leading to inhibition of the conditioned response (CR). Extinction creates a new CS-noUCS memory trace, competing with the initial fear (CS-UCS) memory. Recall of extinction memory and, hence, CR inhibition at later CS encounters is facilitated by contextual stimuli present during extinction training. In line with theoretical predictions derived from animal studies, we show that, after extinction, a CS-evoked engagement of human ventromedial prefrontal cortex (VMPFC) and hippocampus is context dependent, being expressed in an extinction, but not a conditioning, context. Likewise, a positive correlation between VMPFC and hippocampal activity is extinction context dependent. Thus, a VMPFC-hippocampal network provides for context-dependent recall of human extinction memory, consistent with a view that hippocampus confers context dependence on VMPFC.
Perceived control attenuates pain and pain-directed anxiety, possibly because it changes the emotional appraisal of pain. We examined whether brain areas associated with voluntary reappraisal of emotional experiences also mediate the analgesic effect of perceived control over pain. Using functional magnetic resonance imaging, we compared self-controlled noxious stimuli with physically identical stimuli that were externally controlled. Self-controlled stimulation was accompanied by less pain and anxiety and higher activation in dorsal anterior cingulate (dACC), right dorsolateral, and bilateral anterolateral prefrontal (alPFC) cortices. Activation in dACC and right alPFC was negatively correlated with pain intensity ratings. For externally controlled pain, activation in right alPFC was inversely correlated with the participants' general belief to have control over their lives. Our results are consistent with a reappraisal view of control and suggest that the analgesic effect of perceived control relies on activation of right alPFC. Failure to activate right alPFC may explain the maladaptive effects of strong general control beliefs during uncontrollable pain.
Traditionally, anatomical and physiological descriptions of hemispheric specialization have focused on hemispheric asymmetries of local brain structure or local functional properties, respectively. This article reviews the current state of an alternative approach that aims at unraveling the causes and functional principles of hemispheric specialization in terms of asymmetries in connectivity. Starting with an overview of the historical origins of the concept of lateralization, we briefly review recent evidence from anatomical and developmental studies that asymmetries in structural connectivity may be a critical factor shaping hemispheric specialization. These differences in anatomical connectivity, which are found both at the intra- and inter-regional level, are likely to form the structural substrate of different functional principles of information processing in the two hemispheres. The main goal of this article is to describe how these functional principles can be characterized using functional neuroimaging in combination with models of functional and effective connectivity. We discuss the methodology of established models of connectivity which are applicable to data from positron emission tomography and functional magnetic resonance imaging and review published studies that have applied these approaches to characterize asymmetries of connectivity during lateralized tasks. Adopting a model-based approach enables functional imaging to proceed from mere descriptions of asymmetric activation patterns to mechanistic accounts of how these asymmetries are caused.
The aim of this study was to measure the contextual influence of globally coherent motion on visual cortical responses using functional magnetic resonance imaging. Our motivation was to test a prediction from representational theories of perception (i.e. predictive coding) that primary visual responses should be suppressed by top-down influences during coherent motion. We used a sparse stimulus array such that each element could not fall within the same classical receptive field of primary visual cortex neurons (i.e. precluding lateral interactions within V1). This enabled us to attribute differences, in striate cortex responses, to extra-classical receptive field effects mediated by backward connections. In accord with theoretical predictions we were able to demonstrate suppression of striate cortex activations to coherent relative to incoherent motion. These results suggest that suppression of primary visual cortex responses to coherent motion reflect extra-classical effects mediated by backward connections.
Previous studies found normal or even superior performance of autistic patients on visuospatial tasks requiring local search, like the Embedded Figures Task (EFT). A well-known interpretation of this is "weak central coherence", i.e. autistic patients may show a reduced general ability to process information in its context and may therefore have a tendency to favour local over global aspects of information processing. An alternative view is that the local processing advantage in the EFT may result from a relative amplification of early perceptual processes which boosts processing of local stimulus properties but does not affect processing of global context. This study used functional magnetic resonance imaging (fMRI) in 12 autistic adolescents (9 Asperger and 3 high-functioning autistic patients) and 12 matched controls to help distinguish, on neurophysiological grounds, between these two accounts of EFT performance in autistic patients. Behaviourally, we found autistic individuals to be unimpaired during the EFT while they were significantly worse at performing a closely matched control task with minimal local search requirements. The fMRI results showed that activations specific for the local search aspects of the EFT were left-lateralised in parietal and premotor areas for the control group (as previously demonstrated for adults), whereas for the patients these activations were found in right primary visual cortex and bilateral extrastriate areas. These results suggest that enhanced local processing in early visual areas, as opposed to impaired processing of global context, is characteristic for performance of the EFT by autistic patients.
We describe work that addresses the cortical basis for the analysis of auditory objects using 'generic' sounds that do not correspond to any particular events or sources (like vowels or voices) that have semantic association. The experiments involve the manipulation of synthetic sounds to produce systematic changes of stimulus features, such as spectral envelope. Conventional analyses of normal functional imaging data demonstrate that the analysis of spectral envelope and perceived timbral change involves a network consisting of planum temporale (PT) bilaterally and the right superior temporal sulcus (STS). Further analysis of imaging data using dynamic causal modelling (DCM) and Bayesian model selection was carried out in the right hemisphere areas to determine the effective connectivity between these auditory areas. Specifically, the objective was to determine if the analysis of spectral envelope in the network is done in a serial fashion (that is from HG to PT to STS) or parallel fashion (that is PT and STS receives input from HG simultaneously). Two families of models, serial and parallel (16 in total) that represent different hypotheses about the connectivity between HG, PT and STS were selected. The models within a family differ with respect to the pathway that is modulated by the analysis of spectral envelope. After the models are identified, Bayesian model selection procedure is then used to select the 'optimal' model from the specified models. The data strongly support a particular serial model containing modulation of the HG to PT effective connectivity during spectral envelope variation. Parallel work in neurological subjects addresses the effect of lesions to different parts of this network. We have recently studied in detail subjects with 'dystimbria': an alteration in the perceived quality of auditory objects distinct from pitch or loudness change. The subjects have lesions of the normal network described above with normal perception of pitch strength but abnormal perception of the analysis of spectral envelope change.
