Agatha Lenartowicz

Role of prefrontal cortex and the midbrain dopamine system in working memory updating

Humans are adept at switching between goal-directed behaviors quickly and effectively. The prefrontal cortex (PFC) is thought to play a critical role by encoding, updating, and maintaining internal representations of task context in working memory. It has also been hypothesized that the encoding of context representations in PFC is regulated by phasic dopamine gating signals. Here we use multimodal methods to test these hypotheses. First we used functional MRI (fMRI) to identify regions of PFC associated with the representation of context in a working memory task. Next we used single-pulse transcranial magnetic stimulation (TMS), guided spatially by our fMRI findings and temporally by previous event-related EEG recordings, to disrupt context encoding while participants performed the same working memory task. We found that TMS pulses to the right dorsolateral PFC (DLPFC) immediately after context presentation, and well in advance of the response, adversely impacted context-dependent relative to context-independent responses. This finding causally implicates right DLPFC function in context encoding. Finally, using the same paradigm, we conducted high-resolution fMRI measurements in brainstem dopaminergic nuclei (ventral tegmental area and substantia nigra) and found phasic responses after presentation of context stimuli relative to other stimuli, consistent with the timing of a gating signal that regulates the encoding of representations in PFC. Furthermore, these responses were positively correlated with behavior, as well as with responses in the same region of right DLPFC targeted in the TMS experiment, lending support to the hypothesis that dopamine phasic signals regulate encoding, and thereby the updating, of context representations in PFC.

Functional connectivity of hippocampal networks in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) affects brain areas beyond the temporal lobes due to connections of the hippocampi and other temporal lobe structures. Using functional connectivity magnetic resonance imaging (MRI), we determined the changes of hippocampal networks in TLE to assess for a more complete distribution of abnormality.

Inhibition-related activation in the right inferior frontal gyrus in the absence of inhibitory cues

The right inferior frontal gyrus (rIFG) has been hypothesized to mediate response inhibition. Typically response inhibition is signaled by an external stop cue, which provides a top–down signal to initiate the process. However, recent behavioral findings suggest that response inhibition can also be triggered automatically by bottom–up processes. In the present study, we evaluated whether rIFG activity would also be observed during automatic inhibition, in which no stop cue was presented and no motor inhibition was actually required. We measured rIFG activation in response to stimuli that were previously associated with stop signals but which required a response on the current trial (reversal trials). The results revealed an increase in rIFG (pars triangularis) activity, suggesting that it can be activated by associations between stimuli and stopping. Moreover, its role in inhibition tasks is not contingent on the presence of an external stop cue. We conclude that rIFG involvement in stopping is consistent with a role in reprogramming of action plans, which may comprise inhibition, and its activity can be triggered through automatic, bottom–up processing.

The Role of Anterior Cingulate Cortex in Working Memory is Shaped by Functional Connectivity

The anterior cingulate (AC) cortex seems to be similarly engaged by attentional and memory processes. We tested the hypothesis that this common activation is best explained by changes in the regions interacting (functionally connected) with AC. Subjects were tested on two variants of a 2-back working memory task: a standard version with strong attentional demands, and a cued version that more strongly promoted memory retrieval. AC activation, measured with functional MRI, was found in both tasks, although more sustained in the standard condition. The regions functionally connected to the AC, and the relation of these activity patterns to memory performance, were completely different across tasks. In the standard task, the pattern related to a speed-accuracy tradeoff, whereas the connectivity pattern unique to the cued task related only to better accuracy. By virtue of these changing patterns of functional connectivity, the contribution of AC to attention-and memory-driven performance was similarly changed.

Effect of lateralized temporal lobe epilepsy on the default mode network.

The default mode network (DMN) is composed of cerebral regions involved in conscious, resting state cognition. The hippocampus is an essential component of this network. Here, the DMN in TLE is compared to control subjects to better understand its involvement in TLE. We performed resting state connectivity analysis using regions of interest (ROIs) in the retrosplenium/precuneus (Rsp/PCUN) and the ventro-medial pre-frontal cortex (vmPFC) in 36 subjects (11 with right TLE, 12 with left TLE, 13 controls) to delineate the posterior and anterior DMN regions respectively. We found reduced connectivity of the posterior to the anterior DMN in patients with both right and left TLE. However, the posterior and anterior networks were found to be individually preserved. Lateralization of TLE affects the DMN with left TLE demonstrating more extensive networks. These DMN changes may be relevant to altered cognition and memory in TLE and may be relevant to right vs. left TLE differences in cognitive involvement.

Electroencephalography Correlates of Spatial Working Memory Deficits in Attention-Deficit/Hyperactivity Disorder: Vigilance, Encoding, and Maintenance

In the current study we sought to dissociate the component processes of working memory (WM) (vigilance, encoding and maintenance) that may be differentially impaired in attention-deficit/ hyperactivity disorder (ADHD). We collected electroencephalographic (EEG) data from 52 children with ADHD and 47 typically developing (TD) children, ages 7–14 years, while they performed a spatial Sternberg working memory task. We used independent component analysis and time-frequency analysis to identify midoccipital alpha (8–12 Hz) to evaluate encoding processes and frontal midline theta (4–7 Hz) to evaluate maintenance processes. We tested for effects of task difficulty and cue processing to evaluate vigilance. Children with ADHD showed attenuated alpha band event-related desynchronization (ERD) during encoding. This effect was more pronounced when task difficulty was low (consistent with impaired vigilance) and was predictive of memory task performance and symptom severity. Correlated with alpha ERD during encoding were alpha power increases during the maintenance period (relative to baseline), suggesting a compensatory effort. Consistent with this interpretation, midfrontal theta power increases during maintenance were stronger in ADHD and in high-load memory conditions. Furthermore, children with ADHD exhibited a maturational lag in development of posterior alpha power whereas age-related changes in frontal theta power deviated from the TD pattern. Last, subjects with ADHD showed age-independent attenuation of evoked responses to warning cues, suggesting low vigilance. Combined, these three EEG measures predicted diagnosis with 70% accuracy. We conclude that the interplay of impaired vigilance and encoding in ADHD may compromise maintenance and lead to impaired WM performance in this group.

Updating of context in working memory: An event-related potential study

Flexible control of behavior depends on the representation, maintenance, and updating of context information in working memory, which is thought to rely on the prefrontal cortex (PFC). However, in contrast to maintenance, the dynamics of context activation and updating have not been well studied. To identify neural signals associated with context updating, we compared event-related potentials associated with cues that did or did not provide task-relevant context information. The earliest effect of context was detected 200 msec following cue onset and had a scalp topography consistent with a generator in the PFC. Subsequent effects of context were detected at 400-700 msec following cue onset (P3b), with a broad scalp distribution spanning posterior areas, and during the final 300 msec preceding the target, with a probable generator in the medial frontal cortex. We propose that the effect of context on P2 is consistent with the onset of context updating in the PFC. Subsequent components may be indicative of activation of task-relevant posterior regions and context maintenance.

Use of EEG to Diagnose ADHD

Electroencephalography (EEG) has, historically, played a focal role in the assessment of neural function in children with attention deficit hyperactivity disorder (ADHD). We review here the most recent developments in the utility of EEG in the diagnosis of ADHD, with emphasis on the most commonly used and emerging EEG metrics and their reliability in diagnostic classification. Considering the clinical heterogeneity of ADHD and the complexity of information available from the EEG signals, we suggest that considerable benefits are to be gained from multivariate analyses and a focus towards understanding of the neural generators of EEG. We conclude that while EEG cannot currently be used as a diagnostic tool, vast developments in analytical and technological tools in its domain anticipate future progress in its utility in the clinical setting.

Research Review: Use of EEG biomarkers in child psychiatry research – current state and future directions

BACKGROUND Electroencephalography (EEG) and related measures have a long and productive history in child psychopathology research and are currently experiencing a renaissance in interest, particularly for use as putative biomarkers. METHOD AND SCOPE First, the recent history leading to the use of EEG measures as endophenotypes and biomarkers for disease and treatment response are reviewed. Two key controversies within the area of noninvasive human electrophysiology research are discussed, and problems that currently either function as barriers or provide gateways to progress. First, the differences between the main types of EEG measurements (event-related potentials, quantitative EEG, and time-frequency measures) and how they can contribute collectively to better understanding of cortical dynamics underlying cognition and behavior are highlighted. Second, we focus on the ongoing shift in analytic focus to specific cortical sources and source networks whose dynamics are relevant to the clinical and experimental focus of the study, and the effective increase in source signal-to-noise ratio (SNR) that may be obtained in the process. CONCLUSIONS Understanding of these issues informs any discussion of current trends in EEG research. We highlight possible ways to evolve our understanding of brain dynamics beyond the apparent contradictions in understanding and modeling EEG activity highlighted by these controversies. Finally, we summarize some promising future directions of EEG biomarker research in child psychopathology.

Functional Imaging of Sleep Vertex Sharp Transients

OBJECTIVE The vertex sharp transient (VST) is an electroencephalographic (EEG) discharge that is an early marker of non-REM sleep. It has been recognized since the beginning of sleep physiology research, but its source and function remain mostly unexplained. We investigated VST generation using functional MRI (fMRI). METHODS Simultaneous EEG and fMRI were recorded from seven individuals in drowsiness and light sleep. VST occurrences on EEG were modeled with fMRI using an impulse function convolved with a hemodynamic response function to identify cerebral regions correlating to the VSTs. A resulting statistical image was thresholded at Z>2.3. RESULTS Two hundred VSTs were identified. Significantly increased signal was present bilaterally in medial central, lateral precentral, posterior superior temporal, and medial occipital cortex. No regions of decreased signal were present. CONCLUSION The regions are consistent with electrophysiologic evidence from animal models and functional imaging of human sleep, but the results are specific to VSTs. The regions principally encompass the primary sensorimotor cortical regions for vision, hearing, and touch. SIGNIFICANCE The results depict a network comprising the presumed VST generator and its associated regions. The associated regions functional similarity for primary sensation suggests a role for VSTs in sensory experience during sleep.