Scott M. Lewis

Where the brain grows old: decline in anterior cingulate and medial prefrontal function with normal aging.

Even healthy adults worry about declines in mental efficiency with aging. Subjective changes in mental flexibility, self-regulation, processing speed, and memory are often cited. We show here that focal decreases in brain activity occur with normal aging as measured with fluorodeoxyglucose and positron emission tomography. The largest declines localize to a medial network including the anterior cingulate/medial prefrontal cortex, dorsomedial thalamus, and sugenual cingulate/basal forebrain. Declining metabolism in this network correlates with declining cognitive function. The medial prefrontal metabolic changes with aging are similar in magnitude to the hypometabolism found in Mild Cognitive Impairment or Alzheimers disease. These results converge with data from healthy elderly indicating dysfunction in the anterior attention system. The interaction of attention in the anterior cingulate cortex with memory in the medial temporal lobe may explain the global impairment that defines dementia. Despite the implications for an aging population, the neurophysiologic mechanisms of these metabolic decreases remain unknown.

The Effect of Stimulus-Response Compatibility on Cortical Motor Activation

Stimulus-response compatibility (SRC) is a general term describing the relationship between a triggering stimulus and its associated motor response. The relationship between stimulus and response can be manipulated at the level of the set of stimulus and response characteristics (set-level) or at the level of the mapping between the individual elements of the stimulus and response sets (element-level). We used functional magnetic resonance imaging (fMRI) to investigate the effects of SRC on functional activation in cortical motor areas. Using behavioral tasks to separately evaluate set- and element-level compatibility, and their interaction, we measured the volume of functional activation in 11 cortical motor areas, in the anterior frontal cortex, and in the superior temporal lobe. Element-level compatibility effects were associated with significant activation in the pre-supplementary motor area (preSMA), the dorsal (PMd) and ventral (PMv) premotor areas, and the parietal areas (inferior, superior, intraparietal sulcus, precuneus). The activation was lateralized to the right hemisphere for most of the areas. Set-level compatibility effects resulted in significant activation in the inferior frontal gyri, anterior cingulate and cingulate motor areas, the PMd, PMv, preSMA, the parietal areas (inferior, superior, intraparietal sulcus, precuneus), and in the superior temporal lobe. Activation in the majority of these areas was lateralized to the left hemisphere. Finally, there was an interaction between set and element-level compatibility in the middle and superior frontal gyri, in an area co-extensive with the dorsolateral prefrontal cortex, suggesting that this area provided the neural substrate for common processing stages, such as working memory and attention, which are engaged when both levels of SRC are manipulated at once.

Comparison of Finger Tracking Versus Simple Movement Training via Telerehabilitation to Alter Hand Function and Cortical Reorganization After Stroke

Objective. To compare 2 telerehabilitation training strategies, repetitive tracking movements versus repetitive simple movements, to promote brain reorganization and recovery of hand function. Methods. Twenty subjects with chronic stroke and 10 degrees of voluntary finger extension were randomly assigned to receive 1800 telerehabilitation trials over 2 weeks of either computerized tracking training (track group) with the affected finger and wrist involving temporospatial processing to achieve accuracy or movement training (move group) with no attention to accuracy. Following movement training, the move group crossed over to receive an additional 2 weeks of tracking training. Behavioral changes were measured with the Box and Block test, Jebsen Taylor test, and finger range of motion, along with a finger-tracking activation paradigm during fMRI. Results. The track group showed significant improvement in all 4 behavioral tests; the move group improved in the Box and Block and Jebsen Taylor tests. The improvement for the track group in the Box and Block and Jebsen Taylor tests did not surpass that for the move group. A consistent group pattern of brain reorganization was not evident. The move group, after crossing over, did not show further significant improvements. Conclusion . Telerehabilitation may be effective in improving performance in subjects with chronic stroke. Tracking training with reinforcement to enhance learning, however, did not produce a clear advantage over the same amount of practice of random movements. Two weeks of training may be insufficient to demonstrate a behavioral advantage and associated brain reorganization.

Synchronous neural interactions assessed by magnetoencephalography: a functional biomarker for brain disorders

We report on a test to assess the dynamic brain function at high temporal resolution using magnetoencephalography (MEG). The essence of the test is the measurement of the dynamic synchronous neural interactions, an essential aspect of the brain function. MEG signals were recorded from 248 axial gradiometers while 142 human subjects fixated a spot of light for 45-60 s. After fitting an autoregressive integrative moving average (ARIMA) model and taking the stationary residuals, all pairwise, zero-lag, partial cross-correlations (PCC(ij)(0)) and their z-transforms (z(ij)(0)) between i and j sensors were calculated, providing estimates of the strength and sign (positive, negative) of direct synchronous coupling at 1 ms temporal resolution. We found that subsets of z(ij)(0) successfully classified individual subjects to their respective groups (multiple sclerosis, Alzheimers disease, schizophrenia, Sjögrens syndrome, chronic alcoholism, facial pain, healthy controls) and gave excellent external cross-validation results.

The synchronous neural interactions test as a functional neuromarker for post-traumatic stress disorder (PTSD): a robust classification method based on the bootstrap.

Traumatic experiences can produce post-traumatic stress disorder (PTSD) which is a debilitating condition and for which no biomarker currently exists (Institute of Medicine (US) 2006 Posttraumatic Stress Disorder: Diagnosis and Assessment (Washington, DC: National Academies)). Here we show that the synchronous neural interactions (SNI) test which assesses the functional interactions among neural populations derived from magnetoencephalographic (MEG) recordings (Georgopoulos A P et al 2007 J. Neural Eng. 4 349-55) can successfully differentiate PTSD patients from healthy control subjects. Externally cross-validated, bootstrap-based analyses yielded >90% overall accuracy of classification. In addition, all but one of 18 patients who were not receiving medications for their disease were correctly classified. Altogether, these findings document robust differences in brain function between the PTSD and control groups that can be used for differential diagnosis and which possess the potential for assessing and monitoring disease progression and effects of therapy.

Post-traumatic stress disorder: a right temporal lobe syndrome?

In a recent paper (Georgopoulos et al 2010 J. Neural Eng. 7 016011) we reported on the power of the magnetoencephalography (MEG)-based synchronous neural interactions (SNI) test to differentiate post-traumatic stress disorder (PTSD) subjects from healthy control subjects and to classify them with a high degree of accuracy. Here we show that the main differences in cortical communication circuitry between these two groups lie in the miscommunication of temporal and parietal and/or parieto-occipital right hemispheric areas with other brain areas. This lateralized temporal-posterior pattern of miscommunication was very similar but was attenuated in patients with PTSD in remission. These findings are consistent with observations (Penfield 1958 Proc. Natl Acad. Sci. USA 44 51-66, Penfield and Perot 1963 Brain 86 595-696, Gloor 1990 Brain 113 1673-94, Banceaud et al 1994 Brain 117 71-90, Fried 1997 J. Neuropsychiatry Clin. Neurosci. 9 420-8) that electrical stimulation of the temporal cortex in awake human subjects, mostly in the right hemisphere, can elicit the re-enactment and re-living of past experiences. Based on these facts, we attribute our findings to the re-experiencing component of PTSD and hypothesize that it reflects an involuntarily persistent activation of interacting neural networks involved in experiential consolidation.

Chronic vagus nerve stimulation for treatment-resistant depression decreases resting ventromedial prefrontal glucose metabolism

Vagus nerve stimulation (VNS) is used as an adjunctive therapy for treatment-resistant depression (TRD). Its mechanism of action is not fully understood. Longitudinal measurement of changes in brain metabolism associated with VNS can provide insights into this new treatment modality. Eight severely depressed outpatients who were highly treatment-resistant underwent electrical stimulation of the left vagus nerve for approximately one year. The main outcome measures were resting regional brain glucose uptake measured with positron emission tomography (PET) and the 24-item Hamilton Depression Scale. The most significant and extensive change over one year of chronic VNS localized to the ventromedial prefrontal cortex extending from the subgenual cingulate to the frontal pole. This region continued to decline in metabolism even toward the end of the study. Clinically, this cohort showed a trend for improvement. No correlations surfaced between change in glucose uptake and depression scores. However, the sample size was small; none remitted; and the range of depression scores was limited. Chronic VNS as adjunctive therapy in patients with severe TRD produces protracted and robust declines in resting brain activity within the ventromedial prefrontal cortex, a network with dense connectivity to the amygdala and structures monitoring the internal milieu.

Neural Network Modulation by Trauma as a Marker of Resilience Differences Between Veterans With Posttraumatic Stress Disorder and Resilient Controls

IMPORTANCE Posttraumatic stress disorder (PTSD) and resilience reflect 2 distinct outcomes after exposure to potentially traumatic events. The neural mechanisms underlying these different outcomes are not well understood. OBJECTIVE To examine the effect of trauma on synchronous neural interactions for veterans with PTSD and resilient controls using magnetoencephalography. DESIGN Participants underwent diagnostic interviews, a measure of exposure to potentially traumatic events, and magnetoencephalography. SETTING U.S. Department of Veterans Affairs medical center. PARTICIPANTS Eighty-six veterans with PTSD and 113 resilient control veterans recruited from a large Midwestern Medical Center. MAIN OUTCOME MEASURES Multiple regression analyses were performed to examine the effect of lifetime trauma on global and local synchronous neural interactions. In analyses examining the local synchronous neural interactions, the partial regression coefficient indicates the strength and direction of the effect of trauma on the synchronous interactions between the 2 neural signals recorded by a pair of sensors. The partial regression coefficient, or slope, is the primary outcome measure for these analyses. RESULTS Global synchronous neural interactions were significantly modulated downward with increasing lifetime trauma scores in resilient control veterans (P = .003) but not in veterans with PTSD (P = .91). This effect, which was primarily characterized by negative slopes (i.e., decorrelations) in small neural networks, was strongest in the right superior temporal gyrus. Significant negative slopes were more common, stronger, and observed between sensors at shorter distances than positive slopes in both hemispheres (P < .001 for all) for controls but not for veterans with PTSD. CONCLUSIONS. Neural modulation involving decorrelation of neural networks in the right superior temporal gyrus and, to a lesser extent, other areas distinguishes resilient veterans from those with PTSD and is postulated to have an important role in healthy response to trauma.

Choice and stimulus–response compatibility affect duration of response selection

In general, for movements to visual targets, response times increase with the number of possible response choices. However, this rule only seems to hold when an incompatibility exists between the stimulus and response, and is absent when stimulus and response are highly compatible (e.g., when reaching toward the location of the stimulus). Stimulus-response (S-R) compatibility can be manipulated either at the level of stimulus and response characteristics, or at the level of the mapping between elements of the stimulus and response sets. The current study was undertaken to determine the extent of the interaction between choice and each of these two levels of S-R compatibility. Subjects used a joystick to move a cursor in response to two, four or eight possible cues, with S-R compatibility manipulated along two dimensions (type of stimulus, and mapping between stimulus and response sets) in separate blocks of trials. Choice effects were absent when S-R relationships were highly compatible, moderate when incompatible in either of the two dimensions, and greatest when incompatible in both dimensions. These results indicate that choice affects response selection at each stage in the decoding of S-R relationships. Similar but smaller effects were seen for trials in which the stimulus was the same as that presented in the immediately preceding trial, suggesting that repeated stimulus-response transformations are faster and more efficient due to the priming effects of previous trials.

Cerebral cortical mechanisms of copying geometrical shapes: a multidimensional scaling analysis of fMRI patterns of activation

We used multidimensional scaling (MDS) to characterize the integrative neural mechanisms during viewing and subsequently copying nine geometrical shapes. Human subjects initially looked at a central fixation point (“rest” period), then looked at a geometrical shape (“visual” period) which they copied without visual feedback (“copying” period). BOLD signal was recorded from voxels in 28 cortical areas (14 from each hemisphere) using a 4 Tesla magnet. For each voxel, signal ratios of “Visual versus Rest” (VR), and “Copy versus Visual” (CV) were calculated and used to construct two sets of Euclidean distance dissimilarity matrices for the nine shapes, with separate matrices defined for each region of interest (ROI) across subjects. The relations of perceptual and motor aspects of the shapes to MDS dimensions and specific ROIs were assessed using stepwise multiple regressions. The optimal individually scaled (INDSCAL) solutions were 2-dimensional. For the VR condition, MDS dimensions were significantly associated with the presence of crossing in a shape (Dimension 1), and with perimeter, height, cycles, peak segment speed, and horizontal symmetry (Dimension 2). ROIs most prominently associated with these dimensions essentially comprised the medial frontal lobe bilaterally, the inferior frontal gyrus bilaterally, and the left intraparietal sulcus (Dimension 1), and visual areas, including the calcarine sulcus and cuneus bilaterally (Dimension 2). These results document the expected involvement of visual areas and support the hypothesis advanced on the basis of previous findings (Lewis et al. 2003a) that a motor rehearsal of the upcoming shape copying is occurring during this visual presentation period. For the CV condition, practically one motor feature (number of segments drawn) dominated both dimensions, with a secondary engagement of horizontal symmetry in Dimension 1. The right postcentral gyrus, right intraparietal sulcus, right superior parietal lobule and right inferior parietal lobule contributed mostly to Dimension 1; the superior frontal gyrus bilaterally, right middle frontal gyrus, left postcentral gyrus, left inferior parietal lobule contributed mostly to Dimension 2; and the left superior parietal lobule and left intraparietal sulcus contributed to both dimensions approximately equally. CV BOLD activation of ROIs contributing to Dimension 1 (or to both dimensions) was significantly associated with the number of shape segments drawn. Since the direction of movement differs in successively drawn shape segments, the number of segments (minus one) equals the number of changes in the direction of movement. We conclude that this fundamental spatial motor aspect of drawing geometrical shapes is the critical variable, independent of the particular shape drawn, that dominates cortical activation during copying.