Mark J. Lowe

Activity and connectivity of brain mood regulating circuit in depression : A functional magnetic resonance study

BACKGROUND Functional imaging studies indicate that imbalances in cortico-limbic activity and connectivity may underlie the pathophysiology of MDD. In this study, using functional Magnetic Resonance Imaging (fMRI), we investigated differences in cortico-limbic activity and connectivity between depressed patients and healthy controls. METHODS Fifteen unmedicated unipolar depressed patients and 15 matched healthy subjects underwent fMRI during which they first completed a conventional block-design activation experiment in which they were exposed to negative and neutral pictures. Next, low frequency blood oxygenation dependent (BOLD) related fluctuations (LFBF) data were acquired at rest and during steady-state exposure to neutral, positive and negative pictures. LFBF correlations were calculated between anterior cingulate cortex (ACC) and limbic regions--amygdala (AMYG), pallidostriatum (PST) and medial thalamus (MTHAL) and used as a measure of cortico-limbic connectivity. RESULTS Depressed patients had increased activation of cortical and limbic regions. At rest and during exposure to neutral, positive, and negative pictures cortico-limbic LFBF correlations were decreased in depressed patients compared to healthy subjects. CONCLUSIONS The finding of increased activation of limbic regions and decreased LFBF correlations between ACC and limbic regions is consistent with the hypothesis that decreased cortical regulation of limbic activation in response to negative stimuli may be present in depression.

Resting state corticolimbic connectivity abnormalities in unmedicated bipolar disorder and unipolar depression

This study for the first time investigated resting state corticolimbic connectivity abnormalities in unmedicated bipolar disorder (BD) and compared them with findings in healthy controls and unipolar major depressive disorder (MDD) patient groups. Resting state correlations of low frequency BOLD fluctuations (LFBF) in echoplanar functional magnetic resonance (fMRI) data were acquired from a priori defined regions of interests (ROIs) in the pregenual anterior cingulate cortex (pgACC), dorsomedial thalamus (DMTHAL), pallidostriatum (PST) and amygdala (AMYG), to investigate corticolimbic functional connectivity in unmedicated BD patients in comparison to healthy subjects and MDD patients. Data were acquired from 11 unmedicated BD patients [six manic (BDM) and five depressed (BDD)], and compared with data available from 15 unmedicated MDD and 15 healthy subjects. BD patients had significantly decreased pgACC connectivity to the left and right DMTHAL, similar to findings seen in MDD. Additionally, BD patients had decreased pgACC connectivity with the left and right AMYG as well as the left PST. An exploratory analysis revealed that both BDD and BDM patients had decreased connectivity between the pgACC and DMTHAL. The results of the study indicate a common finding of decreased corticolimbic functional connectivity in different types of mood disorders.

Human amygdala activation detected with echo-planar functional magnetic resonance imaging

Echo-Planar functional magnetic resonance imaging (EP-fMRI) was used to study the activity of the amygdala while three normal female subjects viewed alternating blocks of affectively neutral and affectively negative still pictures. Bilateral activation in the amygdala that was significantly correlated with the changing valence of the visual stimuli was found in all three subjects. These findings are consistent with the large corpus of data from non-human studies suggesting that the amygdala is a key structure for extracting the affective significance from external stimuli. This is the first known report of phasic amygdala activation detected with EP-fMRI in normal human subjects responding to affective stimuli.

Antidepressant effect on connectivity of the mood-regulating circuit : An fMRI study

The mechanisms by which antidepressant-induced neurochemical changes lead to physiological changes in brain circuitry and ultimately an antidepressant response remain unclear. This study investigated the effects of sertraline, a selective serotonin reuptake inhibitor antidepressant, on corticolimbic connectivity, using functional magnetic resonance imaging (fMRI). In all, 12 unmedicated unipolar depressed patients and 11 closely matched healthy control subjects completed two fMRI scanning sessions at baseline and after 6 weeks. Depressed patients received treatment with sertraline between the two sessions. During each fMRI session, subjects first completed a conventional block-design experiment. Next, connectivity between cortical and limbic regions was measured using correlations of low-frequency blood oxygen level-dependent (BOLD) fluctuations (LFBF) during continuous exposure to neutral, positive, and negative pictures. At baseline, depressed patients had decreased corticolimbic LFBF correlations compared to healthy subjects during the resting state and on exposure to emotionally valenced pictures. At rest and on exposure to neutral and positive pictures, LFBF correlation between the anterior cingulate cortex and limbic regions was significantly increased in patients after treatment. However, on exposure to negative pictures, corticolimbic LFBF correlations remained decreased in depressed patients. The results of this study are consistent with the hypothesis that antidepressant treatment may increase corticolimbic connectivity, thereby possibly increasing the regulatory influence of cortical mood-regulating regions over limbic regions.

Correlations in low-frequency BOLD fluctuations reflect cortico-cortical connections.

Cross-correlation of low-frequency temporal fluctuations (<0.08 Hz) was used to correlate widely separated anatomic regions during continuous performance of a spatial working memory task. The regions of highest correlation to right-hemisphere dorsolateral prefrontal cortex correspond to the regions of largest baseline signal change in a conventional block-style functional MRI paradigm. Additionally, it is shown that the correlations between elements of the functional network increase during performance of a task that activates the network when compared to a task that does not directly stimulate the functionally connected network.

Reproducibility of fMRI Results across Four Institutions Using a Spatial Working Memory Task

Four U.S. sites formed a consortium to conduct a multisite study of fMRI methods. The primary purpose of this consortium was to examine the reliability and reproducibility of fMRI results. FMRI data were collected on healthy adults during performance of a spatial working memory task at four different institutions. Two sets of data from each institution were made available. First, data from two subjects were made available from each site and were processed and analyzed as a pooled data set. Second, statistical maps from five to eight subjects per site were made available. These images were aligned in stereotactic space and common regions of activation were examined to address the reproducibility of fMRI results when both image acquisition and analysis vary as a function of site. Our grouped and individual data analyses showed reliable patterns of activation in dorsolateral prefrontal cortex and posterior parietal cortex during performance of the working memory task across all four sites. This multisite study, the first of its kind using fMRI data, demonstrates highly consistent findings across sites.

Hemispheric roles in the perception of speech prosody

Speech prosody is processed in neither a single region nor a specific hemisphere, but engages multiple areas comprising a large-scale spatially distributed network in both hemispheres. It remains to be elucidated whether hemispheric lateralization is based on higher-level prosodic representations or lower-level encoding of acoustic cues, or both. A cross-language (Chinese; English) fMRI study was conducted to examine brain activity elicited by selective attention to Chinese intonation (I) and tone (T) presented in three-syllable (I3, T3) and one-syllable (I1, T1) utterance pairs in a speeded response, discrimination paradigm. The Chinese group exhibited greater activity than the English in a left inferior parietal region across tasks (I1, I3, T1, T3). Only the Chinese group exhibited a leftward asymmetry in inferior parietal and posterior superior temporal (I1, I3, T1, T3), anterior temporal (I1, I3, T1, T3), and frontopolar (I1, I3) regions. Both language groups shared a rightward asymmetry in the mid portions of the superior temporal sulcus and middle frontal gyrus irrespective of prosodic unit or temporal interval. Hemispheric laterality effects enable us to distinguish brain activity associated with higher-order prosodic representations in the Chinese group from that associated with lower-level acoustic/auditory processes that are shared among listeners regardless of language experience. Lateralization is influenced by language experience that shapes the internal prosodic representation of an external auditory signal. We propose that speech prosody perception is mediated primarily by the RH, but is left-lateralized to task-dependent regions when language processing is required beyond the auditory analysis of the complex sound.

Resting state sensorimotor functional connectivity in multiple sclerosis inversely correlates with transcallosal motor pathway transverse diffusivity.

Recent studies indicate that functional connectivity using low‐frequency BOLD fluctuations (LFBFs) is reduced between the bilateral primary sensorimotor regions in multiple sclerosis. In addition, it has been shown that pathway‐dependent measures of the transverse diffusivity of water in white matter correlate with related clinical measures of functional deficit in multiple sclerosis. Taken together, these methods suggest that MRI methods can be used to probe both functional connectivity and anatomic connectivity in subjects with known white matter impairment. We report the results of a study comparing anatomic connectivity of the transcallosal motor pathway, as measured with diffusion tensor imaging (DTI) and functional connectivity of the bilateral primary sensorimotor cortices (SMC), as measured with LFBFs in the resting state. High angular resolution diffusion imaging was combined with functional MRI to define the transcallosal white matter pathway connecting the bilateral primary SMC. Maps were generated from the probabilistic tracking employed and these maps were used to calculate the mean pathway diffusion measures fractional anisotropy 〈FA〉, mean diffusivity 〈MD〉, longitudinal diffusivity 〈λ1〉, and transverse diffusivity 〈λ2〉. These were compared with LFBF‐based functional connectivity measures (Fc) obtained at rest in a cohort of 11 multiple sclerosis patients and ∼10 age‐ and gender‐matched control subjects. The correlation between 〈FA〉 and Fc for MS patients was r = −0.63, P < 0.04. The correlation between all subjects 〈λ2〉 and Fc was r = 0.42, P < 0.05. The correlation between all subjects 〈λ2〉 and Fc was r = −0.50, P < 0.02. None of the control subject correlations were significant, nor were 〈FA〉, 〈λ1〉, or 〈MD〉 significantly correlated with Fc for MS patients. This constitutes the first in vivo observation of a correlation between measures of anatomic connectivity and functional connectivity using spontaneous LFBFs. Hum Brain Mapp, 2008.

Comparison of rhyming and word generation with FMRI

Functional magnetic resonance imaging (FMRI) has been successfully used to non‐invasively map language function, but has several disadvantages. These include severe motion sensitivity, which limits overt verbal responses in behavioral paradigms, such as word generation. The lack of overt responses prevents behavioral validation, making data interpretation difficult. Our objective was to compare the FMRI activation patterns of a novel silent rhyme determination task requiring a non‐verbal response, to covert word generation from visually presented letters. Five strongly right‐handed subjects performed both tasks during multi‐slice coronal echo‐planar T2*–weighted FMRI. Single subject activation maps were generated for each task by correlation analysis of single pixel time series to a boxcar reference function. These maps for the two tasks were separately interpolated to 2563, transformed into Talairach space, summed, and thresholded at t>6. Combined activation maps from both tasks showed similar robust perisylvian language area activation, including inferior frontal gyrus, posterior superior temporal lobe, and fusiform gyrus. Subjects performed well on the rhyming task, which activated left hemisphere cortical regions more selectively than the word generation task. The rhyming task showed less activation than the word generation task in areas typically not considered specifically related to language function, such as the dorsolateral prefrontal cortex and anterior cingulate. The rhyming task is a useful tool for brain mapping and clinical applications, potentially more specific to cortical language areas than verbal fluency. Hum. Brain Mapping 10:99–106, 2000.

Reciprocal Effects of Antidepressant Treatment on Activity and Connectivity of the Mood Regulating Circuit: An fMRI Study

It has been hypothesized that one of the effects of antidepressants is to increase functional connectivity between the cortical mood-regulating and the limbic mood-generating regions. One consequence of this antidepressant effect is thought to be decreased limbic activation in response to negative emotional stimuli. Twelve unmedicated unipolar depressed patients and 11 closely matched healthy comparison subjects completed two magnetic resonance imaging (MRI) scanning sessions at baseline and after 6 weeks. Depressed patients received treatment with sertraline between the two sessions. During each MRI session, subjects completed a resting state functional connectivity scan and a conventional block-design negative vs. neutral pictures regional brain activation scan. After 6 weeks of sertraline treatment resting state, functional connectivity between the ACC and limbic regions increased while limbic activation in response to negative versus neutral pictures decreased. The results of this study are consistent with the hypothesis that antidepressant treatment has reciprocal effects on corticolimbic functional connectivity and limbic activation in response to emotional stimuli.