Fish Oil Supplementation Increases Event-Related Posterior Cingulate Activation in Older Adults with Subjective Memory Impairment.

OBJECTIVES: To determine the effects of long-chain omega-3 (LCn-3) fatty acids found in fish oil, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on cortical blood oxygen level-dependent (BOLD) activity during a working memory task in older adults with subjective memory impairment. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Academic medical center. PARTICIPANTS: Healthy older adults (62-80 years) with subjective memory impairment, but not meeting criteria for mild cognitive impairment or dementia. INTERVENTION: Fish oil (EPA+DHA: 2.4 g/d, n=11) or placebo (corn oil, n=10) for 24 weeks. MEASUREMENTS: Cortical BOLD response patterns during performance of a sequential letter n-back working memory task were determined at baseline and week 24 by functional magnetic resonance imaging (fMRI). RESULTS: At 24 weeks erythrocyte membrane EPA+DHA composition increased significantly from baseline in participants receiving fish oil (+31%, p ≤ 0.0001) but not placebo (-17%, p=0.06). Multivariate modeling of fMRI data identified a significant interaction among treatment, visit, and memory loading in the right cingulate (BA 23/24), and in the right sensorimotor area (BA 3/4). In the fish oil group, BOLD increases at 24 weeks were observed in the right posterior cingulate and left superior frontal regions during memory loading. A region-of-interest analysis indicated that the baseline to endpoint change in posterior cingulate cortex BOLD activity signal was significantly greater in the fish oil group compared with the placebo group during the 1-back (p=0.0003) and 2-back (p=0.0005) conditions. Among all participants, the change in erythrocyte EPA+DHA during the intervention was associated with performance in the 2-back working memory task (p = 0.01), and with cingulate BOLD signal during the 1-back (p = 0.005) with a trend during the 2-back (p = 0.09). Further, cingulate BOLD activity was related to performance in the 2-back condition. CONCLUSION: Dietary fish oil supplementation increases red blood cell omega-3 content, working memory performance, and BOLD signal in the posterior cingulate cortex during greater working memory load in older adults with subjective memory impairment suggesting enhanced neuronal response to working memory challenge.

Functional MRI of sustained attention in bipolar mania.

We examined sustained attention deficits in bipolar disorder and associated changes in brain activation assessed by functional magnetic resonance imaging (fMRI). We hypothesized that relative to healthy participants, those with mania or mixed mania would (1) exhibit incremental decrements in sustained attention over time, (2) overactivate brain regions required for emotional processing and (3) progressively underactivate attentional regions of prefrontal cortex. Fifty participants with manic/mixed bipolar disorder (BP group) and 34 healthy comparison subjects (HC group) received an fMRI scan while performing a 15-min continuous performance task (CPT). The data were divided into three consecutive 5-min vigilance periods to analyze sustained attention. Composite brain activation maps indicated that both groups activated dorsal and ventral regions of an anterior-limbic network, but the BP group exhibited less activation over time relative to baseline. Consistent with hypotheses 1 and 2, the BP group showed a marginally greater behavioral CPT sustained attention decrement and more bilateral amygdala activation than the HC group, respectively. Instead of differential activation in prefrontal cortex over time, as predicted in hypothesis 3, the BP group progressively decreased activation in subcortical regions of striatum and thalamus relative to the HC group. These results suggest that regional activation decrements in dorsolateral prefrontal cortex accompany sustained attention decrements in both bipolar and healthy individuals. Stable amygdala overactivation across prolonged vigils may interfere with sustained attention and exacerbate attentional deficits in bipolar disorder. Differential striatal and thalamic deactivation in bipolar disorder is interpreted as a loss of amygdala (emotional brain) modulation by the ventrolateral prefrontal-subcortical circuit, which interferes with attentional maintenance.

Human brain activation accompanying explicitly directed movement sequence learning.

We examined brain activation patterns occurring during the production and encoding of a motor sequence. Participants performed a variant of the serial reaction-time task under two conditions. The first condition was designed to foster the engagement of explicit mechanisms of knowledge acquisition. The second condition was intended to encourage the engagement of implicit learning mechanisms that would be more typical of the standard serial reaction-time task. In the first condition, the acquisition of explicit knowledge about an 8-element ordered sequence led to a significant and rapid decline in reaction time. By contrast, the second condition, the task in which a sequence was presented unbeknownst to participants, did not yield changes in reaction time. Several brain regions, including prefrontal cortex, superior and inferior parietal lobules, and cerebellum, exhibited explicit learning-related activation. The prefrontal cortex and inferior parietal lobules increased their levels of activation between the beginning and end of the experiment, while primary motor, primary sensory, and cerebellar cortex decreased their levels of activation from the beginning to the end of the experiment. We propose a model in which two processes, a learning-related increase and a habituation process might interact to produce the activation patterns observed during movement sequence acquisition. In short, the prefrontal cortex and inferior parietal lobule together direct and recruit superior parietal lobule and cerebellum to encode and perform the sequence. The increased activation in prefrontal cortex and inferior parietal lobule may represent the activity of a working memory circuit that functions in the acquisition and recall of sequence information.

Anterior and posterior callosal contributions to simultaneous bimanual movements of the hands and fingers.

In order to study the role of the corpus callosum in two-handed coordination we tested callosotomy subjects while they attempted to initiate simultaneous discrete movements with both hands. We observed four split-brain patients, including one pre- and post-operatively, as well as normal and epileptic control subjects. Split-brain patients made button presses that were less synchronous than either normal or epileptic controls. Although split-brain patients' average performance did not always differ from control subjects, callosotomy resulted in a 3-fold increase in the variability with which 'simultaneous' movements were initiated. The one subject tested pre- and post-callosotomy showed distinct changes in movement initiation synchrony after both the anterior and the posterior stages of the surgery. These changes suggest that anterior and posterior callosal fibres may make unique contributions to bimanual synchronization, depending on whether responses are self-initiated or in reaction to a visual stimulus. This study demonstrates that neural communication across anterior and posterior fibres of the corpus callosum strongly influences the temporal precision of bimanual coordination. Specifically, callosal transmission affects the degree of bilateral synchrony with which simple simultaneous hand and finger movements are initiated.

Direction information coordinated via the posterior third of the corpus callosum during bimanual movements.

We examined bimanual coordination in a patient before and after each stage of callosotomy surgery. We tested how well the patient coordinated movement direction between the hands. The patient drew symmetrical or asymmetrical figures simultaneously with both hands. Before surgery, symmetrical figures were drawn well and asymmetrical figures were drawn poorly. Following anterior callosotomy, the drawings improved slightly. Symmetrical figures were still drawn well, and asymmetrical ones were still drawn poorly. Thus, spatial integration remained intact despite the loss of interhemispheric communication between frontal cortical sites. After posterior callosotomy, spatial coordination deteriorated significantly. Mirror-image drawings became less symmetrical, while asymmetrical drawings improved. These data indicate that the posterior callosum mediates the coordination of direction information between the hands during bimanual movements. Given the topographical organization of the corpus callosum, this integration is likely carried out by parietal cortex.

Modular organization of cognitive systems masked by interhemispheric integration.

After resection of the corpus callosum, V.J., a left-handed woman with left-hemisphere dominance for spoken language, demonstrated a dissociation between spoken and written language. In the key experiment, words flashed to V.J.'s dominant left hemisphere were easily spoken out loud, but could not be written. However, when the words were flashed to her right hemisphere, she could not speak them out loud, but could write them with her left hand. This marked dissociation supports the view that spoken and written language output can be controlled by independent hemispheres, even though before her hemispheric disconnection, they appeared as inseparable cognitive entities.

Collaboration between the hemispheres of a callosotomy patient. Emerging right hemisphere speech and the left hemisphere interpreter.

Split brain patients who are initially unable to produce speech in their right hemispheres sometimes develop the ability to do so. Patient J.W., the subject of this report, is such a patient. At the time of his callosotomy, J.W. had a language dominant left hemisphere; his right hemisphere could understand both spoken and written language, but he was unable to speak. Fourteen years after his surgery, we found that J.W. was capable of naming approximately 25% of the stimuli presented to his left visual field (LVF). Now, 1 year later, we find that he can name about 60% of such stimuli. This late-developing speech ability appears to be consequence of long-term neural plasticity. However, the subject's extended verbal responses to LVF stimuli seem to result from a collaboration between the hemispheres and to involve the left hemisphere interpreter.

Transcranial magnetic stimulation: delays in visual suppression due to luminance changes.

Transcranial magnetic stimulation (TMS) was used to investigate the delays in visual processing time produced by changes in luminance. By administering a magnetic pulse over the occipital pole 80-140 ms after the onset of visual stimuli, we could suppress perception of a four-digit number within a 30 ms time window. Commensurate with previous studies of visual processing latencies, a drop in luminance from 3.52 logTd to 2.61 logTd delayed the peak of the suppression window by 8.9 ms, while a further drop from 2.61 logTD to 1.75 logTd delayed the peak by an additional 15.4 ms. This study validates the use of TMS as a psychophysical tool.

Left hemisphere representations of emotional facial expressions.

Researchers have suggested that the right hemisphere is superior at processing emotional facial expressions because it contains stored perceptual 'templates' of facial expressions. We tested each hemisphere of a split-brain patient on two tasks involving emotional facial expressions. Both hemispheres performed equally well and significantly above chance matching facial expressions with emotion words. The subject's right hemisphere consistently performed well judging whether two facial expressions were the same or different. His left hemisphere performed poorly on this discrimination task at first, but showed a sharp improvement when the instructions were changed slightly, emphasizing verbal labels for the facial expressions. Results suggest that 'facial expression templates' may not be stored only on the right.

Identification and molecular cloning of a neuropeptide Y homolog that produces prolonged inhibition in Aplysia neurons.

The neuroendocrine bag cell neurons of the marine mollusk Aplysia produce prolonged inhibition that lasts for more than 2 hr. We purified a peptide from the abdominal ganglion that mimics this inhibition. Mass spectrometry and microsequence analysis indicate that the peptide is 40 aa long and is amidated at its carboxyl terminus. It is highly homologous to vertebrate neuropeptide Y (NPY) and other members of the pancreatic polypeptide family. As determined from cloned cDNA, the gene coding for the precursor protein shares a common structural organization with genes encoding precursors of the vertebrate family. The peptides may therefore have arisen from a common ancestral gene. Bag cell neurons are immunoreactive for Aplysia NPY, and Northern blot analysis indicates that as with its vertebrate counterparts, the peptide is abundantly expressed in the CNS. This suggests that peptides related to NPY may have important functions in the nervous system of Aplysia as well as in other invertebrates.

Isolation and partial characterization of neuropeptides that mimic prolonged inhibition produced by bag cell neurons in Aplysia.

The bag cell neurons of the marine mollusk Aplysia are part of a neural system that utilizes four neuropeptides as neurotransmitters. The peptides, derived from the egg-laying hormone/bag cell peptide (ELH/BCP) precursor protein, are released during a 20-min burst discharge of the bag cells and produce several types of responses in various abdominal ganglion neurons. In the identified neurons L3 and L6, bag cell activity produces prolonged inhibition that lasts for more than 2 h. One of the bag cell peptides, alpha-BCP, mediates an early component of the inhibition in these neurons. To identify the co-transmitter mediating the prolonged component of inhibition, we purified material from an acid extract of abdominal ganglia using molecular sizing high-pressure liquid chromatography (HPLC) on TSK 250-125 followed by two steps of reverse-phase HPLC on C4 or C18. We isolated three inhibitory factors that mimic the prolonged component of inhibition. Mass spectroscopy and partial amino acid sequence analysis indicate one factor is ELH [2-36], that is, ELH that lacks the first, N-terminal amino acid. This inhibitory activity was similar in potency to that of ELH and is the first to be described for an ELH-related peptide. The two other factors were approximately 3,300 and 4,700 Da and were effective at 10- and 50-fold lower concentration, respectively, than ELH or its fragment. Amino acid composition analysis suggests that they are not derived from the ELH/BCP precursor protein. The 4,700 Da factor is effective at the lowest concentration and produces an effect that lasts as long as 100 min.(ABSTRACT TRUNCATED AT 250 WORDS)