Seminars

The ability to effectively regulate emotions is a fundamental skill related to physical and psychological health. In this talk, I will present behavioral and fMRI data from several different studies that examined cognitive reappraisal, acceptance, and suppression emotion regulation strategies in healthy controls participants and in the context of randomized trials of cognitive behavioral therapy, mindfulness- based stress reduction, and aerobic exercise as interventions for adults with anxiety disorders. We will also examine the implementation of different types of functional connectivity analytic approaches to probe intervention-related brain mechanism changes.

Dysregulation of emotional processing and its integration with cognitive functions are central features of many mental/emotional disorders associated both with externalizing problems (aggressive, antisocial behaviors) and internalizing problems (anxiety, depression). As Dr. Joseph LeDoux, our invited speaker of this program, wrote in his famous book “Synaptic self: How Our Brains Become Who We Are”—the brain’s synapses—are the channels through which we think, act, imagine, feel, and remember. Synapses encode the essence of personality, enabling each of us to function as a distinctive, integrated individual from moment to moment. Thus, exploring the functioning of synapses leads to the understanding of the mechanism of (patho)physiological function of our brain. In this context, we have investigated the pathophysiology of psychiatric disorders, with particular emphasis on the synaptic function of model mice of various psychiatric disorders such as schizophrenia, autism, depression, and PTSD. Our current interest is how synaptic inputs are integrated to generate the action potential. Because the spatiotemporal organization of neuronal firing is crucial for information processing, but how thousands of inputs to the dendritic spines drive the firing remains a central question in neuroscience. We identified a distinct pattern of synaptic integration in the disease-related models, in which extra-large (XL) spines generate NMDA spikes within these spines, which was sufficient to drive neuronal firing. We experimentally and theoretically observed that XL spines negatively correlated with working memory. Our work offers a whole new concept for dendritic computation and network dynamics, and the understanding of psychiatric research will be greatly reconsidered. The second half of my talk is the development of a novel synaptic tool. Because, no matter how beautifully we can illuminate the spine morphology and how accurately we can quantify the synaptic integration, the links between synapse and brain function remain correlational. In order to challenge the causal relationship between synapse and brain function, we established AS-PaRac1, which is unique not only because it can specifically label and manipulate the recently potentiated dendritic spine (Hayashi-Takagi et al, 2015, Nature). With use of AS-PaRac1, we developed an activity-dependent simultaneous labeling of the presynaptic bouton and the potentiated spines to establish “functional connectomics” in a synaptic resolution. When we apply this new imaging method for PTSD model mice, we identified a completely new functional neural circuit of brain region A→B→C with a very strong S/N in the PTSD model mice. This novel tool of “functional connectomics” and its photo-manipulation could open up new areas of emotional/psychiatric research, and by extension, shed light on the neural networks that determine who we are.

The cognitive neuroscience of conscious perception has seen considerable growth over the past few decades. Confirming an influential hypothesis driven by earlier studies of neuropsychological patients, we have found that the lateral and polar prefrontal cortices play important causal roles in the generation of subjective experiences. However, this basic empirical finding has been hotly contested by researchers with different theoretical commitments, and the differences are at times difficult to resolve. To address the controversies, I suggest one alternative venue may be to look for clinical applications derived from current theories. I outline an example in which we used closed-loop fMRI combined with machine learning to nonconsciously manipulate the physiological responses to threatening stimuli, such as spiders or snakes. A clinical trial involving patients with phobia is currently taking place. I also outline how this theoretical framework may be extended to other diseases. Ultimately, a truly meaningful understanding of the fundamental nature of our mental existence should lead to useful insights for our colleagues on the clinical frontlines. If we use this as a yardstick, whoever loses the esoteric theoretical debates, both science and the patients will always win.

Much of our daily behavior is driven by rewards. The ability to learn to pursue rewarding experiences is, in fact, an essential metric of mental health. Conversely, reduced capacity to engage in adaptive goal-oriented behavior is the hallmark of apathy, and present in the psychotic disorder. The search for its underlying mechanisms has resulted in findings of profound impairments in learning from rewards and the associated blunted activation in key reward areas of the brain of patients with psychosis. An emerging research field has been relying on digital phenotyping tools and ecological momentary assessments (EMA) that map patients’ current mood, behavior and context in the flow of their daily lives. Using these tools, we have started to see a different picture of apathy, one that is exquisitely driven by the environment. For one, reward sensitivity appears to be blunted by stressors, and exposure to undue chronic stress in the daily life may result in apathy in those predisposed to psychosis. Secondly, even patients with psychosis who exhibit clinically elevated levels of apathy are perfectly capable of seeking out and enjoying social interactions in their daily life, if their environment allows them to do so. The use of digital phenotyping tools in combination with neuroimaging of apathy not only allows us to add meanings to the neurobiological findings, but could also help design rational interventions.

Drug addiction is a chronically relapsing disorder characterized by compulsive drug use despite catastrophic personal consequences (e.g., loss of family, job) and even when the substance is no longer perceived as pleasurable. In this talk, I will present results of human neuroimaging studies, utilizing a multimodal approach (neuropsychology, functional magnetic resonance imaging, event-related potentials recordings), to explore the neurobiology underlying the core psychological impairments in drug addiction (impulsivity, drive/motivation, insight/awareness) as associated with its clinical symptomatology (intoxication, craving, bingeing, withdrawal). The focus of this talk is on understanding the role of the dopaminergic mesocorticolimbic circuit, and especially the prefrontal cortex, in higher-order executive dysfunction (e.g., disadvantageous decision-making such as trading a car for a couple of cocaine hits) in drug addicted individuals. The theoretical model that guides the presented research is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex, as related to dopaminergic dysfunction, contribute to the core clinical symptoms in drug addiction. Specifically, our multi-modality program of research is guided by the underlying working hypothesis that drug addicted individuals disproportionately attribute reward value to their drug of choice at the expense of other potentially but no-longer-rewarding stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. In this talk I will also explore whether treatment (as usual) and 6-month abstinence enhance recovery in these brain-behavior compromises in treatment seeking cocaine addicted individuals. Promising neuroimaging studies, which combine pharmacological (i.e., oral methylphenidate, or RitalinTM) and salient cognitive tasks or functional connectivity during resting-state, will be discussed as examples for using neuroimaging for empirically guiding the development of effective neurorehabilitation strategies (encompassing cognitive reappraisal and transcranial direct current stimulation) in drug addiction.

Impulsivity and compulsivity are behavioural traits that underlie many aspects of decision-making and form the characteristic symptoms of Obsessive Compulsive Disorder (OCD) and Gambling Disorder (GD). The neural underpinnings of aspects of reward and avoidance learning under the expression of these traits and symptoms are only partially understood. " "The present study combined behavioural modelling and neuroimaging technique to examine brain activity associated with critical phases of reward and loss processing in OCD and GD. " "Forty-two healthy controls (HC), forty OCD and twenty-three GD participants were recruited in our study to complete a two-session reinforcement learning (RL) task featuring a “probability switch (PS)” with imaging scanning. Finally, 39 HC (20F/19M, 34 yrs +/- 9.47), 28 OCD (14F/14M, 32.11 yrs ±9.53) and 16 GD (4F/12M, 35.53yrs ± 12.20) were included with both behavioural and imaging data available. The functional imaging was conducted by using 3.0-T SIEMENS MAGNETOM Skyra syngo MR D13C at Monash Biomedical Imaging. Each volume compromised 34 coronal slices of 3 mm thickness with 2000 ms TR and 30 ms TE. A total of 479 volumes were acquired for each participant in each session in an interleaved-ascending manner. " " The standard Q-learning model was fitted to the observed behavioural data and the Bayesian model was used for the parameter estimation. Imaging analysis was conducted using SPM12 (Welcome Department of Imaging Neuroscience, London, United Kingdom) in the Matlab (R2015b) environment. The pre-processing commenced with the slice timing, realignment, normalization to MNI space according to T1-weighted image and smoothing with a 8 mm Gaussian kernel. " " The frontostriatal brain circuit including the putamen and medial orbitofrontal (mOFC) were significantly more active in response to receiving reward and avoiding punishment compared to receiving an aversive outcome and missing reward at 0.001 with FWE correction at cluster level; While the right insula showed greater activation in response to missing rewards and receiving punishment. Compared to healthy participants, GD patients showed significantly lower activation in the left superior frontal and posterior cingulum at 0.001 for the gain omission. " " The reward prediction error (PE) signal was found positively correlated with the activation at several clusters expanding across cortical and subcortical region including the striatum, cingulate, bilateral insula, thalamus and superior frontal at 0.001 with FWE correction at cluster level. The GD patients showed a trend of decreased reward PE response in the right precentral extending to left posterior cingulate compared to controls at 0.05 with FWE correction. " " The aversive PE signal was negatively correlated with brain activity in regions including bilateral thalamus, hippocampus, insula and striatum at 0.001 with FWE correction. Compared with the control group, GD group showed an increased aversive PE activation in the cluster encompassing right thalamus and right hippocampus, and also the right middle frontal extending to the right anterior cingulum at 0.005 with FWE correction. " " Through the reversal learning task, the study provided a further support of the dissociable brain circuits for distinct phases of reward and avoidance learning. Also, the OCD and GD is characterised by aberrant patterns of reward and avoidance processing.