The overall goal of our lab is to examine spatio-temporal (i.e. “where and when”) characteristics of distributed neural circuits underlying cognitive and affective functions such as decision making, inhibitory control, language, and emotion perception. Our lab has many interests, including alcohol, Autism Spectrum Disorder, chronic pain, and others. We use multimodal functional imaging including magneto- and electroencephalography (MEG/EEG), functional and structural MRI, and psychophysiological measures of autonomic functions. The synergistic approach allows precise insight into on-line dynamics of these processes, with implications for individualized prevention strategies and pharmacogenetics.
In collaboration with Dr. Axel Mueller's lab we are investigating the neural correlates of language processing in individuals diagnosed with Austism Spectrum Disorder (ASD).
We have also collaborated with Dr. Thereasa Cronan's lab to investigate the effects of a treatment-based intervention program in individuals with fibromyalgia, as well as underlying biomarkers of symptoms.
If you are interested in participating in a study, please contact psych.STBIL@sdsu.edu (see the contact page for more info).
Click on the links below to learn more about the research we perform in the lab!
Our research focuses on the spatio-temporal characteristics underlying cognitive and executive functions in general, and as they pertain to alcohol effects. The synergistic approach based on integration of different brain imaging techniques is especially well-suited for obtaining highly precise insight into on-line dynamics of these processes, with an emphasis on location and sequence of alcohol-related impairments.
Our work, along with other evidence, shows that alcohol intoxication impairs decision making. When preferred or automatic responses must be overridden in lieu of a different response, alcohol interferes with this goal-directed behavior, and results in impaired self-control. Consequences of impaired self-control may be the inability to stop oneself from drinking. Our studies employ a battery of tasks which require participants to engage their cognitive control while we collect neuroimaging data, which is also integrated with personality measures and genetics.
Decision conflict in ACC
Acute alcohol intoxication particularly affects a region of the brain known as the anterior cingular cortex (ACC; noted by green arrow in figure), which is thought to perform conflict monitoring and decision making functions. We have found that power in theta and beta frequency bands are both reduced under alcohol, and theta power is increased under greater cognitive load; the ACC is particularly affected by alcohol under cognitive load.
Response Inhibition: Prefrontal Cortex
In contrast, response inhibition and action cancellation engage a partially different neurofunctional system. It is right-lateralized and it includes inferior frontal cortex and supplementary motor cortex. In tasks such as Go/NoGo which require response inhibition, successfully withholding a prepotent response elicits theta power in a strongly right-lateralized network. Alcohol is also found to reduce theta in these regions during response inhibition.
Alcohol intoxication is associated with disinhibited, impulsive behavior. In this multimodal study, magnetoencephalography (MEG) was combined with structural MRI to examine the acute effects of alcohol on theta-band (4-7Hz) dynamics underlying inhibitory control, errors, and post-error optimization. Adult social drinkers participated in the Go/NoGo task during alcohol challenge.
Right-lateralized theta power elicited by successful response inhibition (NoGo) was attenuated by alcohol. Post-error engagement of cognitive control was reflected in increased dorsal ACC theta and accuracy, which was abolished by alcohol.
Effects of alcohol intoxication on decision conflict as a function of the COMT Val158Met genotype
We are currently investigating differences in dopamine availability, referenced by participants' genotype for the COMT gene. This polymorphic gene codes for the amount of COMT enzyme is produced, which breaks down dopamine in the synapse. By comparing participants who are homozygous for either the Met or Val allele, we hope to elucidate how the amount of dopamine availability affects one's response to alcohol during these tasks and during rest.
Related Publications
Marinkovic, K., & Rosen, B. Q. "Theta oscillatory dynamics of inhibitory control, error processing, and post-error adjustments: Neural underpinnings and alcohol-induced dysregulation." Alcoholism: Clinical and Experimental Research (May 2022) PDF
Rosen, B. Q., Padovan N., and Marinkovic K. "Alcohol Hits You When It Is Hard: Intoxication, Task Difficulty, and Theta Brain Oscillations." Alcoholism-Clinical and Experimental Research 40, no. 4 (Apr 2016): 743-52.
Rosen, Burke Q., Ryan O'Hara, Sanja Kovacevic, Andrew Schulman, Nevena Padovan, and Ksenija Marinkovic. "Oscillatory Spatial Profile of Alcohol's Effects on the Resting State: Anatomically-Constrained Meg." Alcohol 48, no. 2 (Mar 2014): 89-97.
Kovacevic, Sanja, Sheeva Azma, Andrei Irimia, Jason Sherfey, Eric Halgren, and Ksenija Marinkovic. "Theta Oscillations Are Sensitive to Both Early and Late Conflict Processing Stages: Effects of Alcohol Intoxication." PLOS One 7, no. 8 (Aug 27 2012).
Marinkovic, K., Rickenbacher, E., Azma, S., Elinor A. "Acute Alcohol Intoxication Impairs Top-Down Regulation of Stroop Incongruity as Revealed by Blood Oxygen Level-Dependent Functional Magnetic Resonance Imaging." Human Brain Mapping 33, no. 2 (Feb 2012): 319-33.
Marinkovic, K., S. Azma, S. Kovacevic, E. Rickenbacher, J. Sherfey, A. Dale, and E. Halgren. "When the Executive Gets Drunk: Effects of Acute Intoxication on Cognitive Neurodynamics." Alcoholism-Clinical and Experimental Research 35, no. 6 (Jun 2011): 283A-83A.
Marinkovic, K., E. Rickenbacher, E. Artsy, and S. Azma. "Effects of Alcohol Intoxication on Saccadic Control: An fMRI Study." Alcoholism-Clinical and Experimental Research 33, no. 6 (Jun 2009): 88A-88A.
Alcohol Use Disorder
Studies of abstinent alcoholic individuals have indicated that excessive, chronic drinking can lead to brain damage on multiple levels, including atrophy and white-matter damage. The neuroimaging evidence from our research suggests that deficient activation of limbic structures inside the temporal lobes may underlie emotional abnormalities in abstinent long-term alcoholics including difficulties in accurate perception of emotional expressions. Misreading facial cues can escalate interpersonal conflict, creating liability for impaired social interaction and continued drinking. Future studies will determine to what degree these problems are the result of neural changes due to excessive alcohol consumption, or whether they precede the onset of alcoholism.
Related Publications
Marinkovic, Ksenija, Marlene Oscar-Berman, Trinity Urban, Cara E. O'Reilly, Julie A. Howard, Kayle Sawyer, and Gordon J. Harris. "Alcoholism and Dampened Temporal Limbic Activation to Emotional Faces." Alcoholism-Clinical and Experimental Research 33, no. 11 (Nov 2009): 1880-92.
This line of research focuses on examining the neural dynamics of cognitive and affective functions in young adults as a function of binge drinking by using electroencephalography (EEG). A battery of tasks are administered to assess various aspects of cognitive (e.g., memory functioning, inhibitory control) and affective functions in young adults who engage in binge drinking. Deficits in neural systems subserving different dimensions of cognitive and emotional processes, primarily those oscillating at theta (4-7 Hz) frequency band, are detected.
Emotional processing
Binge drinking is selectively associated with attenuated event-related theta power elicited by emotional (vs. neutral) pictures across all scalp sites, although no group difference are observed on the subjective feelings towards the pictures. Such reduction in theta power for emotional (vs. neutral) photos is positively correlated with the binge drinkers’ self-reported number of binge episodes during the past six months.
Memory Retrieval
Binge drinking (BD) and light drinking (LD) participants complete a recognition task in which they judge whether they have seen the pictures during an emotional rating task they perform 48 hrs ago. During this memory retrieval session, BD group displays a decreased differential theta power for the old pictures that are successfully recognized vs. those that are forgotten as compared with LD group, particularly at frontal sites. These results suggest a linkage of binge drinking and undermined frontal theta oscillations that support memory retrieval processes.
Memory Encoding
The same participants underwent a second retrieval session six months after the initial encoding session. Notably, the BD group exhibitied reduced theta oscillations and phase synchronization during the first presentation of images that they were able to remember six months later. Furthermore, the difference in evoked theta between remembered and forgotten images (SME) negatively correlated with the maximum number of drinks consumed in a day participants reported in the last six months. These findings suggest that memory encoding in binge drinkers may be characterized by inefficient network-level interactive engagement of brain areas responsible for memory formation, which may result from excitation/inhibition dysregulation as a function of increased drinking.
Response Inhibition
In a Go/NoGo task which frequently requires the inhibiting of a prepotent motor response, NoGo (response inhibition) trials elicit much greater theta (4-7 Hz) activity than Go (response activation) trials. However, Binge Drinkers (BD) exhibit attenuated theta power, specifically on NoGo trials compared to Light Drinkers (LD). However, no group differences are seen in Go trials, suggesting that binge drinking selectively impairs response inhibition.
Allostasis
Acute alcohol intoxication descreases neural responsivity due to the pharamcological effects of alcohol. However, according to the allostasis model, chronic and repeated binge drinking can result in adaptive changes persisting beyond the acute drinking episode. In accordance with this model, the brain downregulates GABA-mediated inhibitory signaling and upregulates excitatory glutamatergic function, leading to increased neural excitability.
In support of this theory, our lab utilized a study which presented visual stimuli to sober light drinkers and binge drinkers. The findings revealed that the early visual response was attenuated in binge drinkers compared to light drinkers. This early response suggests heitghtened neural excitability, thereby corroborating the allostasis model in sober binge drinkers.
Cognitive Control
A sample of heavy episodic drinkers (HED) and light episodic drinkers (LD) participated in a color naming Stroop task, where a series of color words were presented in several different font colors. Participants were then required to respond with the color of the font each word was written in. The challenge for this task comes when a color word is written in a different font color (e.g. Red or Blue). In these incongruent conditions, participants have to inhibit the automatic tendency to read the word in order to respond with the font color, which tests cognitive control.
HEDs demonstrated higher levels of activity in the bilateral ventrolateral prefrontal cortex and thalamus during the incongruent condition. These brain regions have been previously implicated in cognitive control, and heightened activation could indicate dysfunction within this system.
GABA Concentration
Acute alcohol intoxication increases inhibition mediated by gamma-amino butryic acid (GABA) and decreases excitatory glutamatergic effects. It has been hypothesized that repeated and frequent binge drinking episodes leads to excitatory/inhibitory balance even while sober. A previous paper of from our lab found evidence of heightened excitability among sober binge drinkers, however we published another paper which found reduced GABA concentration directly using the MRS method. Additionally, it was found that GABA concentration correlated with average reported drinks per week.
Related Publications
Huang, S., White, D. R., & Marinkovic, K. (2022). Alterations of theta power and synchrony during encoding in young adult binge drinkers: Subsequent memory effects associated with retrieval after 48 h and 6 months. Front Psychol, 13, 1061016. doi:10.3389/fpsyg.2022.1061016. PDF
Holcomb L, Huang S, Cruz SM, Marinkovic K. (2019) Neural oscillatory dynamics of inhibitory control in young adult binge drinkers. Biological Psychology. PDF
Huang, S., Holcomb, L.A., Cruz, S.M., & Marinkovic, K. "Altered Oscillatory Brain Dynamics of Emotional Processing in Young Binge Drinkers." Cogn Affect Behav Neurosci (Nov 2017): 1-15 PDF
Molnar, S.M., Beaton, L.E., Happer, J.P., Holcomb, L.A., Huang, S., Arienzo, D., & Marinkovic, K. "Behavioral and Brain Activity Indices of Cognitive Control Deficits in Binge Drinkers." Brain Sci 8 no. 1 (Jan 2018) PDF
Face stimuli have captured a great deal of attention in the neuroimaging field, partly resulting from the hotly debated idea that faces are processed in a "face-specific" manner by dedicated brain areas. Indeed, efficient and correct appraisal of face identity and emotional expressions is of great importance to social primates, including humans. Our research and other evidence suggest that faces are processed in a series of successive stages engaging multiple brain areas in an interactive manner. The face-sensitive processing stage is activated at about 170ms after stimulus onset and is situated in the temporal lobe, between early visual cortex and later multimodal cortices that perform cognitive integration with the context.
Related Publications
Marinkovic, Ksenija, Maureen G. Courtney, Thomas Witzel, Anders M. Dale, and Eric Halgren. "Spatio-Temporal Dynamics and Laterality Effects of Face Inversion, Feature Presence and Configuration, and Face Outline." Frontiers in Human Neuroscience 8:868 (Nov 10 2014).
Marinkovic, Ksenija, Marlene Oscar-Berman, Trinity Urban, Cara E. O'Reilly, Julie A. Howard, Kayle Sawyer, and Gordon J. Harris. "Alcoholism and Dampened Temporal Limbic Activation to Emotional Faces." Alcoholism-Clinical and Experimental Research 33, no. 11 (Nov 2009): 1880-92.
Halgren E, Raij T, Marinkovic K, Jousmäki V, Hari R. Cognitive response profile of the human fusiform face area as determined by MEG. Cereb Cortex. 2000; 10(1):69-81.
Klopp, J., K. Marinkovic, P. Chauvel, V. Nenov, and E. Halgren. "Early Widespread Cortical Distribution of Coherent Fusiform Face Selective Activity." Human Brain Mapping 11, no. 4 (Dec 2000): 286-93. PDF
Halgren, E., A. M. Dale, M. I. Sereno, R. B. H. Tootell, K. Marinkovic, and B. R. Rosen. "Location of Human Face-Selective Cortex with Respect to Retinotopic Areas." Human Brain Mapping 7, no. 1 (1999 1999): 29-37. PDF
Klopp, J., E. Halgren, K. Marinkovic, and V. Nenov. "Face-Selective Spectral Changes in the Human Fusiform Gyrus." Clinical Neurophysiology 110, no. 4 (Apr 1999): 676-82. PDF
Language is essential to our communication with others and to our conceptualization of the world. Through words we acquire a multitude of information, articulate our thoughts or feelings and delight in mirth when sharing jokes. When comparing the neural dynamics of understanding written vs. spoken words, the activity starts in sensory-specific areas and progresses towards the simultaneously active supramodal regions in temporal and prefrontal brain regions. "Top-down" guidance from the prefrontal areas facilitates simultaneous lexical, semantic and contextual integration with the goal of rapid comprehension of verbal input.
Language entails much more complexity than understanding individual words, as they are arranged in sentences and discourse. Understanding jokes, for example, relies on semantic, mnemonic, inferential, and emotional contributions of multiple brain areas. In addition to the left temporal and prefrontal regions, funny punch lines activate a "second take" processing in the right prefrontal cortex in order to detect and resolve the clever "twist" they contain. Coherent integration of the intended meaning and a sense of amusement may emerge from the dynamic interaction of these regions with special contributions from the right prefrontal region.
The following "brain movie" is brain activation over time while people view and react to visual stimuli. The activation begins in the occipital lobe and moves forward through the prefrontal cortex. ...
Related Publications
Marinkovic, Ksenija.. "Spatiotemporal Dynamics of Word Processing in the Human Cortex." Neuroscientist 10, no. 2 (Apr 2004): 142-52.
Marinkovic, Ksenija, Burke Q. Rosen, Brendan Cox, and Donald J. Hagler, Jr. "Spatio-Temporal Processing of Words and Nonwords: Hemispheric Laterality and Acute Alcohol Intoxication." Brain Research 1558 (Apr 16 2014): 18-32.
Marinkovic, Ksenija, Burke Q. Rosen, Brendan Cox, and Sanja Kovacevic. "Event-Related Theta Power During Lexical-Semantic Retrieval and Decision Conflict Is Modulated by Alcohol Intoxication: Anatomically Constrained Meg." Frontiers in Psychology 3 (2012 2012).
Marinkovic, Ksenija, Sharelle Baldwin, Maureen G. Courtney, Thomas Witzel, Anders M. Dale, and Eric Halgren. "Right Hemisphere Has the Last Laugh: Neural Dynamics of Joke Appreciation." Cognitive Affective & Behavioral Neuroscience 11, no. 1 (Mar 2011): 113-30.
Halgren, E., C. M. Wang, D. L. Schomer, S. Knake, K. Marinkovic, J. L. Wu, and I. Ulbert. "Processing Stages Underlying Word Recognition in the Anteroventral Temporal Lobe." Neuroimage 30, no. 4 (May 1 2006): 1401-13.
Marinkovic, K., R. P. Dhond, A. M. Dale, M. Glessner, V. Carr, and E. Halgren. "Spatiotemporal Dynamics of Modality-Specific and Supramodal Word Processing." Neuron 38, no. 3 (May 8 2003): 487-97.
Dhond, R. P., R. L. Buckner, A. M. Dale, K. Marinkovic, and E. Halgren. "Spatiotemporal Maps of Brain Activity Underlying Word Generation and Their Modification During Repetition Priming." Journal of Neuroscience 21, no. 10 (May 15 2001): 3564-71. PDF
Our work on Autism Spectrum Disorder (ASD) uses the combined spatial and temporal strengths of anatomically constrained MEG (aMEG) to assess neural functioning. This on-going series of publications utilizes several tasks administered during scans which probe language processing and cognitive functions.
Language
ASD is characterized by difficulties in social communication, and language impairments are common. A sample of adolescents with ASD and typically developing peers took part in a lexical decision task. The task involved the presentation of standard words (SW), animal words (AN), and pseudo words (PW, e.g. "stigor"). Adolescents with ASD demonstrated increased theta in various brain regions impicated in language processing, lower N400m, and increased bilateral activation. These results point to deficiences and alterations in linguistic processing.
Response Conflict
The lexical decision task mentioned above also required participants to respond to SW and AN using their left index and middle fingers respectively. Adolescents with ASD exhibited greater theta in the anterior cingulate cortex and the ipsilateral motor cortex compared to TD adolescents. These results point to enchanced cognitive engagement, as well as suboptimally organized motor circuitry.
Related Publications
You, Y., Correas, A., White, D. R., Wagner, L. C., Jao Keehn, R. J., Rosen, B. Q., . . . Marinkovic, K. (2023). Mapping access to meaning in adolescents with autism: Atypical lateralization and spatiotemporal patterns as a function of language ability. NeuroImage: Clinical, 39, 103467.
Yuqi You, Angeles Correas, R Joanne Jao Keehn, Laura C Wagner, Burke Q Rosen, Lauren E Beaton, Yangfeifei Gao, William T Brocklehurst, Inna Fishman, Ralph-Axel Müller, Ksenija Marinkovic, MEG Theta during Lexico-Semantic and Executive Processing Is Altered in High-Functioning Adolescents with Autism, Cerebral Cortex, (Oct 19 2020). https://doi.org/10.1093/cercor/bhaa279
In conjunction with Dr. Thereasa Cronan's lab, we used electroencephalography (EEG) to investigate the underlying causes of fibromyalgia syndrome (FMS). FMS is associated with chronic pain and cognitive problems often known as "fibro fog". Because analgesics have been shown to be ineffective at treating the pain associated with FMS, it has been proposed that the pain-related symptoms are instead related to central nervous system dysregulation.
Acute Hypersensitivity
A sample of mostly women with FM, as well as a matched non-FM control group, took part in a task which combined auditory and somatosensory stimuli, designed as a classical conditioning experiment. Participants first heard either a high or low tone, and were administered an "uncomfortable, not painful" stimulation to their shin, depending on the tone pairing. Participants with FM rated the painfulness of these stimulations higher than the control group. Additionally, they exhibited more extreme p50s and n100s as well as sympathetics nervous system arousal. These measures also all correlated with FM profile- a single factor consolidating various aspects of FM (pain, anxiety, depression, etc.).
Related Publications
Marinkovic, K., Woodruff, D., White, D. R., Caudle, M. M., & Cronan, T. (2023). Neural indices"pdfs/Marinkovic-2023.pdf" "pdfs/Marinkovic-2023.pdf" of multimodal sensory and autonomic hyperexcitability in fibromyalgia. Neurobiology of Pain, 14, 100140.
During the COVID-19 pandemic, our lab started a project in order to investigate the neural indices of long COVID, also referred to as post-acute sequelae of COVID-19 (PASC). This is an on-going project spanning multiple technologies, methods and tasks. The sample included in the results below was composed of by mostly, otherwise healthy adults who reported mild PASC symptoms after clearing acute COVID-19 infection. The results also involve the use of previously acquired control groups.
Reduced GABA
Participants recieved an MRS scan to determine the concentration of GABA related metabolites in vivo. It was found that participants with PASC had less GABA than the control sample, and measures of GABA negatively correlated with depression. Lowered GABA suggests cortical hyperexcitability, which may result neuroinflammation stemming from the body's immune system response to COVID-19.
Related Publications
Marinkovic, K., Woodruff, D., White, D. R., Caudle, M. M., & Cronan, T. (2023). Neural indices"pdfs/Marinkovic-2023.pdf" "pdfs/Marinkovic-2023.pdf" of multimodal sensory and autonomic hyperexcitability in fibromyalgia. Neurobiology of Pain, 14, 100140.
