Camellia Clark

Nocturnal catecholamines and immune function in insomniacs, depressed patients, and control subjects.

Insomnia predicts cardiovascular and non-cardiovascular disease mortality. This study evaluated EEG sleep, nocturnal sympathetic activity, and daytime measures of immune function in subjects with primary insomnia (n = 17) and patients with current major depression (n = 14) as compared to controls (n = 31). Insomniacs showed disordered sleep continuity along with nocturnal increases of average levels of circulating norepinephrine and decreases of natural killer cell responses, whereas depressed patients showed declines of natural killer cell activity, but no differences of EEG sleep or nocturnal catecholamines as compared to controls. Impairments of sleep efficiency correlated with nocturnal elevations of norepinephrine in the insomniacs but not in the depressives or controls. These data indicate that insomnia is associated with nocturnal sympathetic arousal and declines of natural immunity, and further support the role of sleep in the regulation of sympathetic nervous and immune system functioning.

Clinical and Physiological Consequences of Rapid Tryptophan Depletion

We review here the rapid tryptophan depletion (RTD) methodology and its controversial association with depressive relapse. RTD has been used over the past decade to deplete serotonin (5-hydroxy-tryptamine, or 5-HT) in humans and to probe the role of the central serotonin system in a variety of psychiatric conditions. Its current popularity was stimulated by reports that RTD reversed the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) in remitted patients with a history of depression but not in patients treated with antidepressants which promote catecholaminergic rather than serotonergic neurotransmission (such as tricyclic antidepressants or buproprion). However, RTD has inconsistent effects in terms of full clinical relapse in depressed patients. Pooling the data from all published reports, patients who are either unmedicated and/or fully remitted are much less likely to experience relapse (7 of 61, or ∼9%) than patients who are recently medicated and partially remitted (63 of 133, or ∼47%; although, the numbers here may reflect patient overlap between reports). Recently remitted patients who have been treated with non-pharmacological therapies such as total sleep deprivation, electroconvulsive therapy, or bright light therapy also do not commonly show full clinical relapse with RTD. We briefly review RTD effects in other psychiatric disorders, many of which are treated with SSRIs. There is accumulating evidence to suggest that RTD affects central serotonergic neurotransmission. Nevertheless, many questions remain about the ability of RTD to reverse the beneficial effects of SSRIs or MAOIs, or to induce symptoms in unmedicated symptomatic or asymptomatic patients.

Quantitative Evaluation of Automated Skull-Stripping Methods Applied to Contemporary and Legacy Images: Effects of Diagnosis, Bias Correction, and Slice Location

Performance of automated methods to isolate brain from nonbrain tissues in magnetic resonance (MR) structural images may be influenced by MR signal inhomogeneities, type of MR image set, regional anatomy, and age and diagnosis of subjects studied. The present study compared the performance of four methods: Brain Extraction Tool (BET; Smith [ 2002 ]: Hum Brain Mapp 17:143–155); 3dIntracranial (Ward [ 1999 ] Milwaukee: Biophysics Research Institute, Medical College of Wisconsin; in AFNI); a Hybrid Watershed algorithm (HWA, Segonne et al. [ 2004 ] Neuroimage 22:1060–1075; in FreeSurfer); and Brain Surface Extractor (BSE, Sandor and Leahy [ 1997 ] IEEE Trans Med Imag 16:41–54; Shattuck et al. [ 2001 ] Neuroimage 13:856–876) to manually stripped images. The methods were applied to uncorrected and bias‐corrected datasets; Legacy and Contemporary T1‐weighted image sets; and four diagnostic groups (depressed, Alzheimers, young and elderly control). To provide a criterion for outcome assessment, two experts manually stripped six sagittal sections for each dataset in locations where brain and nonbrain tissue are difficult to distinguish. Methods were compared on Jaccard similarity coefficients, Hausdorff distances, and an Expectation‐Maximization algorithm. Methods tended to perform better on contemporary datasets; bias correction did not significantly improve method performance. Mesial sections were most difficult for all methods. Although AD image sets were most difficult to strip, HWA and BSE were more robust across diagnostic groups compared with 3dIntracranial and BET. With respect to specificity, BSE tended to perform best across all groups, whereas HWA was more sensitive than other methods. The results of this study may direct users towards a method appropriate to their T1‐weighted datasets and improve the efficiency of processing for large, multisite neuroimaging studies. Hum. Brain Mapping, 2005.

Measurement of cerebral perfusion with arterial spin labeling: Part 2. Applications

Arterial spin labeling (ASL) uses magnetic resonance imaging methods to measure cerebral blood flow (CBF) non-invasively. ASL CBF validly localizes brain function and may be especially useful for studies where the time frame of behavioral change is more than a few minutes, such as in longitudinal and treatment studies. ASL measures of cerebral perfusion are highly accurate in detecting lesion laterality in temporal lobe epilepsy, stenotic-occlusive disease, and brain tumors. Among lesioned patients, ASL CBF has excellent concurrent validity when correlated with CBF measured by Positron Emission Tomography or with dynamic susceptibility-weighted magnetic resonance. ASL CBF can predict tumor grading in vivo and can predict six-month response to the surgical treatment of brain tumors. ASLs capability to selectively and non-invasively tag flow in major vessels may refine the monitoring of treatment of cerebrovascular disease and brain tumors. Conclusions about the utility of ASL are limited by the small sample sizes of the studies currently in the literature and by the uncertainty caused by the effect of brain disease on transit times of the magnetic tag. As the method evolves, ASL techniques will likely become more widely used in clinical research and practice.

Effects of a Tryptophan-Free Amino Acid Drink Challenge on Normal Human Sleep Electroencephalogram and Mood

BACKGROUND Serotonin has been implicated in the regulation of sleep and mood. In animals a tryptophan-free amino acid drink (TFD) challenge has been found to reduce brain serotonin. We hypothesized this TFD would produce alterations in electroencephalographic (EEG) sleep commonly associated with depression, i.e. an enhancement of rapid eye movement (REM) sleep, and adversely affect mood ratings in humans. METHODS We investigated the effects of a TFD challenge in 11 healthy male subjects on EEG sleep and mood (assessed by Profile of Mood States). All subjects received on separate occasions an experimental drink containing approximately 100 g of an amino acid mixture (100% TFD) and a control drink containing one fourth strength (25% TFD) of the experimental drink 5 hours prior to sleep (6:00 PM). RESULTS Both drinks significantly decreased plasma tryptophan levels 5 hours postchallenge (11:00 PM). Both drinks significantly decreased REM latency, and the 25% TFD also increased REM time and REM% compared to baseline. No significant changes were found in subjective ratings of depression; however, subjects reported confusion and tension and a decrease in elation, vigor, and friendliness compared with baseline. CONCLUSIONS These TFD findings further support the involvement of serotonin deficiency in EEG sleep findings commonly seen in depression.

A Technique for the Deidentification of Structural Brain MR Images

Due to the increasing need for subject privacy, the ability to deidentify structural MR images so that they do not provide full facial detail is desirable. A program was developed that uses models of nonbrain structures for removing potentially identifying facial features. When a novel image is presented, the optimal linear transform is computed for the input volume (Fischl et al. [ 2002 ]: Neuron 33:341–355; Fischl et al. [ 2004 ]: Neuroimage 23 (Suppl 1):S69–S84). A brain mask is constructed by forming the union of all voxels with nonzero probability of being brain and then morphologically dilated. All voxels outside the mask with a nonzero probability of being a facial feature are set to 0. The algorithm was applied to 342 datasets that included two different T1‐weighted pulse sequences and four different diagnoses (depressed, Alzheimers, and elderly and young control groups). Visual inspection showed none had brain tissue removed. In a detailed analysis of the impact of defacing on skull‐stripping, 16 datasets were bias corrected with N3 (Sled et al. [ 1998 ]: IEEE Trans Med Imaging 17:87–97), defaced, and then skull‐stripped using either a hybrid watershed algorithm (Ségonne et al. [ 2004 ]: Neuroimage 22:1060–1075, in FreeSurfer) or Brain Surface Extractor (Sandor and Leahy [ 1997 ]: IEEE Trans Med Imaging 16:41–54; Shattuck et al. [ 2001 ]: Neuroimage 13:856–876); defacing did not appreciably influence the outcome of skull‐stripping. Results suggested that the automatic defacing algorithm is robust, efficiently removes nonbrain tissue, and does not unduly influence the outcome of the processing methods utilized; in some cases, skull‐stripping was improved. Analyses support this algorithm as a viable method to allow data sharing with minimal data alteration within large‐scale multisite projects. Hum Brain Mapp 2007.

Sleep Deprivation, EEG, and Functional MRI in Depression: Preliminary Results

One night of total or partial sleep deprivation (SD) produces temporary remissions in 40–60% of patients with major depression. Two unmedicated patients with major depression and a matched control received quantitative perfusion MR images at baseline and after one night of partial SD (PSD). A reduction ⩾30% in the 17-item Hamilton Depression Rating Scale (omitting sleep and weight loss items) defined antidepressant response. Theory, techniques, strengths and weaknesses of quantitative perfusion MRI are described in detail. At baseline, the responder exhibited elevated perfusion covering ventral anterior cingulate/medial frontal cortex; the controls maximal perfusion area was markedly smaller. The nonresponders perfusion was lowest of all, particularly ventrally. PSD decreased perfusion over much of the responders hyperperfused area but did not change the nonresponders scan. These preliminary findings are consistent with previous SD studies using PET and SPECT.

Decreased Perfusion in Young Alcohol-Dependent Women as Compared With Age-Matched Controls

Aim: To use the superior spatial resolution of magnetic resonance imaging (MRI) to examine differences in cerebral perfusion between young alcohol dependent and normal women. Methods: Eight alcohol dependent women and 8 controls (all ages 18–25) received single-slice resting perfusion-weighted MRI (directly proportional to brain blood flow), with slices located above the corpus callosum. Results: Alcohol-dependent women had decreased perfusion in prefrontal and left parietal regions. Conclusions: Reduced perfusion has not previously been reported in young, physically healthy alcohol dependent females, yet is consistent with previously reported decreased cerebral activity in alcohol dependence.

Preliminary evidence of an association between increased REM density and poor antidepressant response to partial sleep deprivation.

BACKGROUND One night of total sleep deprivation or of late-night partial sleep deprivation (PSD) produces a temporary remission in approximately 40-60% of patients with major depressive disorder; however, little is known about polysomnography (PSG) characteristics of responders to these types of sleep deprivation (SD). METHODS Twenty-three unmedicated unipolar patients (17-item Hamilton Depression Rating Scale (HDRS17) >16) and 14 normal controls underwent 1 night of late-night PSD (awake after 3 a.m.) Subjects underwent baseline PSG and received the HDRS17 at standard times before and after PSD. Clinical response was defined as a reduction of >30% in the modified HDRS17 (omitting sleep and weight loss items) following PSD. RESULTS The 12 responders and 11 nonresponders did not differ from each other significantly on baseline HDRS17 or PSG variables. The only PSG variable correlating with percent decrease in modified HDRS17 was baseline REM density (Pearsons r=-0.52, n=23, P=0.01.) In other words, the lower the baseline REM density, the more robust the antidepressant response was. LIMITATIONS Subject numbers are relatively small. CONCLUSIONS Increased REM density, which reflects the number of rapid eye movements per epoch of REM sleep, may be a physiological marker for severity or poor prognosis in a variety of psychiatric disorders, including relapse in recovering alcoholics, suicidality in schizophrenia, and poor response to PSD or interpersonal psychotherapy in depression.

Is there a relationship between delta sleep at night and afternoon cerebral blood flow, assessed by HMPAO-SPECT in depressed patients and normal control subjects? Preliminary data.

We wished to explore the relationships between waking HMPAO uptake and visually scored polysomnography. We hypothesized that HMPAO activity would correlate positively with slow wave sleep measures the same night. Eight unmedicated unipolar patients with current DSM-IV major depression (17-item Hamilton Depression Rating Scale score 21.5+/-2.9) and seven control subjects received polysomnography on 2 consecutive nights. On the afternoon following the adaptation night, subjects received cerebral SPECT, with 15 mCi Tc-99m-HMPAO injected while subjects performed the Continuous Performance Task. Patients and control subjects did not significantly differ on demographic, polysomnographic, and SPECT variables. Slow wave sleep measures correlated positively (Spearmans) with global and regional tracer activity for depressed (n = 8), control (n = 7) and combined groups (n = 15); in other words, the greater the global or regional afternoon HMPAO uptake, the greater the slow wave sleep measures were the same night. In addition, the greater the waking afternoon global or regional HMPAO activity, the faster subjects fell asleep and the less Stage 2% they had. In patients, global and regional HMPAO activity correlated positively with REM density. Positive correlations between waking tracer activity and subsequent slow wave measures are consistent with previous hypotheses linking slow wave sleep with brain energy conservation and restoration. Further study is needed to determine whether these functional relationships differ in depression.