Seung Suk Kang

Evidence of disrupted functional connectivity in the brain after combat-related blast injury

Non-impact blast-related mild traumatic brain injury (mTBI) appears to be present in soldiers returning from deployments to Afghanistan and Iraq. Although mTBI typically results in cognitive deficits that last less than a month, there is evidence that disrupted coordination of brain activity can persist for at least several months following injury (Thatcher et al., 1989, 2001). In the present study we examined whether neural communication may be affected in soldiers months after blast-related mTBI, and whether coordination of neural function is associated with underlying white matter integrity. The investigation included an application of a new time-frequency based method for measuring electroencephalogram (EEG) phase synchronization (Aviyente et al., 2010) as well as fractional anisotropy measures of axonal tracts derived from diffusion tensor imaging (DTI). Nine soldiers who incurred a blast-related mTBI during deployments to Afghanistan or Iraq were compared with eight demographically similar control subjects. Despite an absence of cognitive deficits, the blast-related mTBI group exhibited diminished EEG phase synchrony of lateral frontal sites with contralateral frontal brain regions suggesting diminished interhemispheric coordination of brain activity as a result of blast injury. For blast injured (i.e., blast-related mTBI) soldiers we found that EEG phase synchrony was associated with the structural integrity of white matter tracts of the frontal lobe (left anterior thalamic radiations and the forceps minor including the anterior corpus callosum). Analyses revealed that diminished EEG phase synchrony was not the consequence of combat-stress symptoms (e.g., post-traumatic stress and depression) and commonly prescribed medications. Results provide evidence for poor coordination of frontal neural function after blast injury that may be the consequence of damaged anterior white matter tracts.

Disrupted functional connectivity for controlled visual processing as a basis for impaired spatial working memory in schizophrenia

Although regional brain abnormalities underlying spatial working memory (SWM) deficits in schizophrenia have been identified, little is known about which brain circuits are functionally disrupted in the SWM network in schizophrenia. We investigated SWM-related interregional functional connectivity in schizophrenia using functional magnetic resonance imaging (fMRI) data collected during a memory task that required analysis of spatial information in object structure. Twelve schizophrenia patients and 11 normal control subjects participated. Patients had SWM performance deficits and deficient neural activation in various brain areas, especially in the high SWM load condition. Examination of the covariation of regional brain activations elicited by the SWM task revealed evidence of functional disconnection between prefrontal and posterior visual association areas in schizophrenia. Under low SMW load, we found reduced functional associations between dorsolateral prefrontal cortex (DLPFC) and inferior temporal cortex (ITC) in the right hemisphere in patients. Under high SWM load, we found evidence for further functional disconnection in patients, including additional reduced functional associations between left DLPFC and right visual areas, including the posterior parietal cortex (PPC), fusiform gyrus, and V1, as well as between right inferior frontal cortex and right PPC. Greater prefrontal-posterior cortical functional connectivity was associated with better SWM performance in controls, but not in patients. These results suggest that prefrontal-posterior functional connectivity associated with the maintenance and control of visual information is central to SWM, and that disruption of this functional network underlies SWM deficits in schizophrenia.

Abnormal mechanisms of antisaccade generation in schizophrenia patients and unaffected biological relatives of schizophrenia patients

Although errant saccadic eye movements may mark genetic factors in schizophrenia, little is known about abnormal brain activity that precedes saccades in individuals with genetic liability for schizophrenia. We investigated electrophysiological activity preceding prosaccades and antisaccades in schizophrenia patients, first-degree biological relatives of schizophrenia patients, and control subjects. Prior to antisaccades, patients had reduced potentials over lateral prefrontal cortex. Smaller potentials were associated with worse antisaccade performance. Relatives also exhibited reduced pre-saccadic potentials over lateral frontal cortex but additionally had reduced potentials over parietal cortex. Both patients and relatives tended toward increased activity over orbital frontal cortex prior to saccades. Results are consistent with lateral prefrontal dysfunction marking genetic liability for schizophrenia and underlying deficient saccadic control.

Abnormal cortical neural synchrony during working memory in schizophrenia

OBJECTIVE To better understand the origins of working memory (WM) impairment in schizophrenia we investigated cortical oscillatory activity in people with schizophrenia (PSZ) while they performed a WM task requiring encoding, maintenance, and retrieval/manipulation processes of spatial information. METHODS We examined time-frequency synchronous energy of cortical source signals that were derived from magnetoencephalography (MEG) localized to cortical regions using WM-related hemodynamic responses and individualized structural head-models. RESULTS Compared to thirteen healthy controls (HC), twelve PSZ showed performance deficits regardless of WM-load or duration. During encoding, PSZ had early theta and delta event-related synchrony (ERS) deficits in prefrontal and visual cortices which worsened with greater memory load and predicted WM performance. During prolonged maintenance of material, PSZ showed deficient beta event-related desynchrony (ERD) in dorsolateral prefrontal, posterior parietal, and visual cortices. In retrieval, PSZ showed reduced delta/theta ERS in the anterior prefrontal and ventral visual cortices and diminished gamma ERS in the premotor and posterior parietal cortices. CONCLUSIONS Although beta/gamma cortical neural oscillatory deficits for maintenance/retrieval are evident during WM, the abnormal prefrontal theta-frequency ERS for encoding is most predictive of poor WM in schizophrenia. SIGNIFICANCE Time-frequency-spatial analysis identified process- and frequency-specific neural synchrony abnormalities underlying WM deficits in schizophrenia.

Abnormal early brain responses during visual search are evident in schizophrenia but not bipolar affective disorder

People with schizophrenia show deficits in processing visual stimuli but neural abnormalities underlying the deficits are unclear and it is unknown whether such functional brain abnormalities are present in other severe mental disorders or in individuals who carry genetic liability for schizophrenia. To better characterize brain responses underlying visual search deficits and test their specificity to schizophrenia we gathered behavioral and electrophysiological responses during visual search (i.e., Span of Apprehension [SOA] task) from 38 people with schizophrenia, 31 people with bipolar disorder, 58 biological relatives of people with schizophrenia, 37 biological relatives of people with bipolar disorder, and 65 non-psychiatric control participants. Through subtracting neural responses associated with purely sensory aspects of the stimuli we found that people with schizophrenia exhibited reduced early posterior task-related neural responses (i.e., Span Endogenous Negativity [SEN]) while other groups showed normative responses. People with schizophrenia exhibited longer reaction times than controls during visual search but nearly identical accuracy. Those individuals with schizophrenia who had larger SENs performed more efficiently (i.e., shorter reaction times) on the SOA task suggesting that modulation of early visual cortical responses facilitated their visual search. People with schizophrenia also exhibited a diminished P300 response compared to other groups. Unaffected first-degree relatives of people with bipolar disorder and schizophrenia showed an amplified N1 response over posterior brain regions in comparison to other groups. Diminished early posterior brain responses are associated with impaired visual search in schizophrenia and appear to be specifically associated with the neuropathology of schizophrenia.

Impaired retrieval processes evident during visual working memory in schizophrenia

Prominent working memory (WM) deficits have been observed in people with schizophrenia (PSZ) across multiple sensory modalities, including the visuospatial realm. Electrophysiological abnormalities noted during early visual processing as well as later cognitive functions in PSZ may underlie deficiencies in WM ability, though the mechanisms linking behavior to neural responses are not well understood. WM dysfunction has also been observed in biological relatives of PSZ (REL) and therefore may be a manifestation of genetic liability for the disorder. We administered a delayed response visuospatial WM task to 23 PSZ, 30 of their REL, and 37 healthy controls (CTRL) to better understand the contributions of neural abnormalities to WM performance deficits associated with schizophrenia. PSZ performed more poorly on the WM task and failed to effectively process distractor stimuli as well as CTRL and REL. N1 electrophysiological responses to probes during retrieval differentiated the type and locations of stimuli presented during encoding in CTRL. Retrieval N1 responses in PSZ, however, failed to do so, while retrieval responses in REL showed more pronounced differentiation of stimulus features during encoding. Furthermore, neural responses during retrieval predicted behavioral performance in PSZ and REL, but not CTRL. These results suggest that retrieval processes are particularly important to efficient visuospatial WM function in PSZ and REL, and support further investigation of WM retrieval as a potential target for improving overall WM function through clinical intervention.

Misinterpreting schizophrenia relatives' impairments

We recently had the pleasure to read Dr. Ma and colleagues’ study of deficits in the relatives of patients with schizophrenia [Ma et al., 2007]. In this study, the researchers evaluated 207 schizophrenia patients, 287 of these patients’ non-psychotic parents and 133 controls on a number of clinical neuropsychological tests. While there was a broad range of impairments in the schizophrenia patients, their parents showed poor performance on a much smaller subset of tests, including the Stroop test, the Verbal Fluency test, the Tower of Hanoi, and the Wisconsin Card Sorting test. The authors interpreted this to mean that the unexpressed genetic liability to schizophrenia was expressed as a ‘‘selective’’ deficit and implicated a prefrontal cortical dysfunction. We agree with the authors that understanding the behavioral impact of the genetic liability to schizophrenia is an important goal [Snitz et al., 2006], and their interpretation was in no way outside the bounds of common practice. In this letter we hope to show that, no matter how common, the practice of inferring that a particular cognitive mechanism or brain system is associated with the unexpressed genetic liability to schizophrenia based on such data is flawed. Importantly, this practice poses an opportunity cost to the field that detracts from the effort to build a cumulative science of the brain systems associated with genetic liability to this debilitating disorder. The flawed inference is a version of the psychometric confound described by Chapman and Chapman [1978]. This confound can occur if the tasks being compared have different degrees of discriminating power. Discriminating power is the capacity to distinguish between two groups and depends on several test properties; it increases generally linearly with reliability, loglinearly with variance and the number of items, and as an inverted u-shaped curve with accuracy. This presents a problem because even tasks that putatively measure specific abilities—say set-shifting or spatial memory—also measure non-specific abilities such as motivation, attention, and strategy formation. One may misinterpret a larger group difference on the set-shifting task as reflecting a deficit in that particular ability, when it may as easily be the result of a group difference in a non-specific ability measured with greater discriminating power. To illustrate the impact of the psychometric confound in neuropsychological testing, we used a computer simulation in which the patient group had a fixed 1.5 SD impairment, and the parents had a fixed 0.75 SD impairment in their latent ability (see Fig. 1). Simply by changing the characteristics of the task used to measure this latent ability, the measured effect sizes changed. Thus, the same impairment in latent ability across several tasks (‘‘A’’ through ‘‘G’’ in the Fig. 1) can result in a pattern of deficits that is very similar to that published by Ma and colleagues (see their Fig. 1) and commonly seen elsewhere to support the inference of a specific deficit. Notice, that although our simulation parameters were not particularly selected to duplicate the tests used by Ma, our Figure incorporates their use of a z-score transformation to compare the extent of the deficit across tasks. This illustrates the principle that despite this transformation, the apparent deficit waxes and wanes across psychometric variants of tasks that measure the exact same latent ability. Although clinical neuropsychological tasks have many superficial differences, data from such batteries do not address the possibility that these contrasts all reflect a general factor measured with different amounts of discriminating power. This point has been raised before in the context of understanding the nature of the cognitive deficits in schizophrenia [Chapman and Chapman, 1978], but it is increasingly important to incorporate into experimental design as we contemplate a future with ever more neuroimaging and molecular genetic studies focused on the unexpressed genetic liability to schizophrenia. Discerning specific cognitive deficits associated with this liability has been shown to be possible, may be extremely useful, and may increase the power of association studies [MacDonald et al., 2007]. However this will take deeper consideration and further refinement of behavioral tasks. Off-the-shelf neuropsychological tests are ill-suited to shine a light into this cave.

Transcendental meditation for veterans with post-traumatic stress disorder.

Objective: Transcendental Meditation (TM) is a mental technique using a mantra to facilitate meditation. TM has a potential for treating symptoms of posttraumatic stress disorder (PTSD), but its clinical efficacy remains to be clarified. This pilot study evaluated the acceptability, preliminary effectiveness, and neurophysiology of TM for veterans with PTSD. Method: Twenty-nine veterans (20.7% female) were recruited from a major medical center and enrolled in the study. TM instruction was provided by certified TM teachers from the Maharishi Foundation and consisted of 8 weeks of individual and group-based meditation instruction and practice. Outcomes were assessed at baseline, during treatment, posttreatment, and at 2-month follow-up, and included clinical interviews, self-report questionnaires, and electroencephalography (EEG) recorded during resting and meditation states. Results: From baseline to posttreatment, participants reported reductions in PTSD symptoms, experiential avoidance, and depressive and somatic symptoms, as well as increases on measures of mindfulness and quality of life. Gains were either maintained or continued to improve through the 2-month follow-up. Compared to baseline, EEG spectral power increased in low-frequency bands (1–7 Hz) at posttreatment and follow-up and only during meditation states suggesting TM-specific changes in brain state associated with the intervention. Conclusions: TM appears to be an acceptable and effective treatment for veterans with PTSD that warrants further study regarding specific outcomes and beneficial changes in brain function.

Preliminary Evidence for Limbic-Frontal Hyperexcitability in Psychogenic Nonepileptic Seizure Patients

Objectives. The goal of the current pilot project was to probe the resting-state magnetoencephalography (MEG) in individuals with psychogenic nonepileptic seizures (PNES) and ascertain if there is evidence for frontal temporal cortical hyperexcitability, as evidenced by increased focal coherence in these regions. Methods. Six patients with PNES and without any evidence of epilepsy were included. Nine healthy control (HC) subjects (age matched as a group) were also included. Subjects underwent 10 minutes of eyes open and 10 minutes of eyes closed MEG recording without any specific cognitive tasks (ie, resting state). Results. Analysis shows posterior-occipital alpha power to be decreased but fronto-temporal delta/theta power increased in people with PNES compared with HC subjects. Analyses of mean interregional functional connectivity of 54 brain regions, patients with PNES tended to have reduced mean coherence in extra-fronto-temporal regions (ex-FTRs) while increased mean coherence in fronto-temporal regions (FTRs) compared with HC. Furthermore, all 6 patients with PNES had their highest coherence structure within the FTRs. This is in contrast to the HC subjects where only 3 of the 9 subjects had their highest coherence value structure in the FTRs (χ2 = 6.67, P = .010). Conclusions. The above findings are consistent with a disbalance between frontotemporal and posterior brain regions in this population with possible increased excitability in the FTRs. The data support the need for further investigations of the pathophysiology of PNES. The identification of a biomarker for PNES would not only provide for more informed therapeutic approaches, but it could also eliminate the stigma associated with the diagnosis of PNES.

Reduced P3b brain response during sustained visual attention is associated with remote blast mTBI and current PTSD in U.S. military veterans

HighlightsNeural correlates of sustained visual attention in veterans with blast mTBI and/or PTSD were examined.P3b amplitude comparably reduced in veterans with blast mTBI and/or PTSD compared to controls.P3b amplitude reduction during a DS‐CPT may index generalized brain pathology in mTBI/PTSD. ABSTRACT Approximately 275,000 American service members deployed to Iraq or Afghanistan have sustained a mild traumatic brain injury (mTBI), with 75% of these incidents involving an explosive blast. Combat‐related mTBI is frequently associated with comorbid mental health disorders, especially posttraumatic stress disorder (PTSD). Attention problems, including sustained attention, are common cognitive complaints of veterans with TBI and PTSD. The present study sought to examine neural correlates of sustained attention in veterans with blast mTBI and/or current PTSD. In 124 veterans of Operations Enduring and Iraqi Freedom (OEF/OIF), we examined event‐related potentials (ERPs) elicited by targets and non‐targets during performance of a degraded‐stimulus continuous performance task (DS‐CPT). Four groups, consisting of veterans with blast‐related mTBI only, current PTSD only, both blast mTBI and PTSD, and a control group, were studied. Compared to all other groups, blast mTBI only participants were more likely to respond regardless of stimulus type during the DS‐CPT. During target detection, the three mTBI/PTSD groups showed reduced amplitude of the P3b (i.e., P300) ERP at Pz compared to the control group. P3b of the three affected groups did not differ from each other. These results suggest that parietal P3b amplitude reduction during target detection in the DS‐CPT task may be an index of brain pathology after combat trauma, yet the diminished brain response fails to differentiate independent effects of blast‐related mTBI or severity of PTSD symptomatology.