A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression.

Target identification and contact selection are known contributors to variability in efficacy across different clinical indications of deep brain stimulation surgery. A retrospective analysis of responders to subcallosal cingulate deep brain stimulation (SCC DBS) for depression demonstrated the common impact of the electrical stimulation on a stereotypic connectome of converging white matter bundles (forceps minor, uncinate fasciculus, cingulum and fronto-striatal fibers). To test the utility of a prospective connectomic approach for SCC DBS surgery, this pilot study used the four-bundle tractography 'connectome blueprint' to plan surgical targeting in 11 participants with treatment-resistant depression. Before surgery, targets were selected individually using deterministic tractography. Selection of contacts for chronic stimulation was made by matching the post-operative probabilistic tractography map to the pre-surgical deterministic tractography map for each subject. Intraoperative behavioral responses were used as a secondary verification of location. A probabilistic tract map of all participants demonstrated inclusion of the four bundles as intended, matching the connectome blueprint previously defined. Eight of 11 patients (72.7%) were responders and 5 were remitters after 6 months of open-label stimulation. At one year, 9 of 11 patients (81.8%) were responders, with 6 of them in remission. These results support the utility of a group probabilistic tractography map as a connectome blueprint for individualized, patient-specific, deterministic tractography targeting, confirming retrospective findings previously published. This new method represents a connectomic approach to guide future SCC DBS studies.

Differential functional connectivity within an emotion regulation neural network among individuals resilient and susceptible to the depressogenic effects of early life stress.

BACKGROUND: Early life stress (ELS) is a significant risk factor for depression. The effects of ELS exposure on neural network organization have not been differentiated from the effect of depression. Furthermore, many individuals exposed to ELS do not develop depression, yet the network organization patterns differentiating resiliency versus susceptibility to the depressogenic effects of ELS are not clear. METHOD: Women aged 18-44 years with either a history of ELS and no history of depression (n = 7), a history of ELS and current or past depression (n = 19), or a history of neither ELS nor depression (n = 12) underwent a resting-state 3-T functional magnetic resonance imaging (fMRI) scan. An emotion regulation brain network consisting of 21 nodes was described using graph analyses and compared between groups. RESULTS: Group differences in network topology involved decreased global connectivity and hub-like properties for the right ventrolateral prefrontal cortex (vlPFC) and decreased local network connectivity for the dorsal anterior cingulate cortex (dACC) among resilient individuals. Decreased local connectivity and increased hub-like properties of the left amygdala, decreased hub-like properties of the dACC and decreased local connectivity of the left vlPFC were observed among susceptible individuals. Regression analyses suggested that the severity of ELS (measured by self-report) correlated negatively with global connectivity and hub-like qualities for the left dorsolateral PFC (dlPFC). CONCLUSIONS: These preliminary results suggest functional neural connectivity patterns specific to ELS exposure and resiliency versus susceptibility to the depressogenic effects of ELS exposure.

Assessing in-session rumination and its effects on CBT for depression.

The study evaluated if rumination of patients during therapy (i.e., in-session rumination) relates to whether or not they do less well in CBT treatment. We developed a reliably assessed in-session rumination observational measure and evaluated its relationship to depression over the course of CBT. Rated sessions came from 63 treatment-naïve patients with major depressive disorder who participated in CBT in the PReDICT study (Dunlop et al., 2017). In-session rumination was operationalized as repetitive, negative, and passive talking about depressive topics. Trained undergraduates rated the intensity and duration of in-session rumination occurring during 57 initial therapy sessions (i.e., session one) and 45 sessions in the middle of treatment (i.e., session eight). The observational ratings were sufficiently reliable (all ICCs > 0.69). Mixed model results indicated that greater intensity of in-session rumination during the initial treatment session predicted higher levels of subsequent clinician-rated depressive symptoms (p < .023). Regression results indicated that greater intensity and duration of in-session rumination at session 8 significantly predicted higher clinician-rated symptoms at end of treatment (p's < 0.02). In-session rumination intensity and duration were not, however, related to subsequent self-reported depressive symptoms. The results support efforts to identify which patients might benefit from rumination-specific interventions.

Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression.

Chronic deep brain stimulation (DBS) of subgenual cingulate white matter results in dramatic remission of symptoms in some previously treatment-resistant depression patients. The effects of stimulation may be mediated locally or via corticocortical or corticosubcortical connections. We use tractography to define the likely connectivity of cingulate regions stimulated in DBS-responsive patients using diffusion imaging data acquired in healthy control subjects. We defined 2 distinct regions within anterior cingulate cortex based on anatomical connectivity: a pregenual region strongly connected to medial prefrontal and anterior midcingulate cortex and a subgenual region with strongest connections to nucleus accumbens, amygdala, hypothalamus, and orbitofrontal cortex. The location of electrode contact points from 9 patients successfully treated with DBS lies within this subgenual region. The anatomical connectivity of the subgenual cingulate region targeted with DBS for depression supports the hypothesis that treatment efficacy is mediated via effects on a distributed network of frontal, limbic, and visceromotor brain regions. At present, targeting of DBS for depression is based on landmarks visible in conventional magnetic resonance imaging. Preoperatively acquired diffusion imaging for connectivity-based cortical mapping could improve neurosurgical targeting. We hypothesize that the subgenual region with greatest connectivity across the distributed network described here may prove most effective.

Differential limbic--cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders.

BACKGROUND: Affective disorders are associated with comorbidity of depression and anxiety symptoms. Positron emission tomography resting-state studies in affective disorders have generally failed to isolate specific symptom effects. Emotion provocation studies in healthy volunteers have produced variable results, due to differences in experimental paradigm and instructions. METHODS: To better delineate the neural correlates of sad mood and anxiety, this study used autobiographical memory scripts in eight healthy women to generate sadness, anxiety, or a neutral relaxed state in a within-subject design. RESULTS: Sadness and anxiety, when contrasted to a neutral emotional state, engaged a set of distinct paralimbic-cortical regions, with a limited number of common effects. Sadness was accompanied by specific activations of the subgenual cingulate area (BA) 25 and dorsal insula, specific deactivation of the right prefrontal cortex BA 9, and more prominent deactivation of the posterior parietal cortex BAs 40/7. Anxiety was associated with specific activations of the ventral insula, the orbitofrontal and anterior temporal cortices, specific deactivation of parahippocampal gyri, and more prominent deactivation of the inferior temporal cortex BAs 20/37. CONCLUSIONS: These findings are interpreted within a model in which sadness and anxiety are represented by segregated corticolimbic pathways, where a major role is played by selective dorsal cortical deactivations during sadness, and ventral cortical deactivations in anxiety.

Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response.

BACKGROUND: Treatment of major depression with antidepressants is generally associated with a delay in onset of clinical response. Functional brain correlates of this phenomenon have not been previously characterized. METHODS: Time course of changes in brain glucose metabolism were measured using positron emission tomography in hospitalized unipolar depressed patients treated with fluoxetine. Time-specific and response-specific effects were examined at 1 and 6 weeks of treatment. RESULTS: Changes were seen over time, and characterized by three distinct patterns: 1) common changes at 1 and 6 weeks, 2) reversal of the 1-week pattern at 6 weeks, and 3) unique changes seen only after chronic treatment. Fluoxetine responders and nonresponders, similar at 1 week, were differentiated by their 6-week pattern. Clinical improvement was uniquely associated with limbic and striatal decreases (subgenual cingulate, hippocampus, insula, and pallidum) and brain stem and dorsal cortical increases (prefrontal, parietal, anterior, and posterior cingulate). Failed response was associated with a persistent 1-week pattern and absence of either subgenual cingulate or prefrontal changes. CONCLUSIONS: Chronic treatment and clinical response to fluoxetine was associated with a reciprocal pattern of subcortical and limbic decreases and cortical increases. Reversal in the week-1 pattern at 6 weeks suggests a process of adaptation in specific brain regions over time in response to sustained serotonin reuptake inhibition. The inverse patterns in responders and nonresponders also suggests that failure to induce these adaptive changes may underlie treatment nonresponse.

Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for obsessive compulsive disorder.

BACKGROUND: As interventions for severe, treatment-refractory obsessive compulsive disorder (OCD), neurosurgical procedures are associated with only modest efficacy. The purpose of this study was to identify cerebral metabolic correlates as potential predictors of treatment response to anterior cingulotomy for OCD. METHODS: Clinical data were analyzed in the context of a retrospective design. Subjects were 11 patients who underwent stereotactic anterior cingulotomy for OCD. Symptom severity was measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) before and at approximately 6 months postoperative. Preoperative F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) data were available. Statistical parametric mapping methods were used to identify loci of significant correlation between preoperative regional cerebral metabolism and postoperative reduction in Y-BOCS scores. RESULTS: One locus within right posterior cingulate cortex was identified, where preoperative metabolism was significantly correlated with improvement in OCD symptom severity following cingulotomy. Specifically, higher preoperative rates of metabolism at that locus were associated with better postoperative outcome. CONCLUSIONS: A possible predictor of treatment response was identified for patients with OCD undergoing anterior cingulotomy. Further research, utilizing a prospective design, is indicated to determine the validity and reliability of this finding. If confirmed, an index for noninvasively predicting response to cingulotomy for OCD would be of great value.

Comparison of [11C]diprenorphine and [11C]carfentanil binding to opiate receptors in humans by positron emission tomography.

The kinetics and regional distribution of [11C]carfentanil, a mu-selective opiate receptor agonist, and [11C]diprenorphine, a nonselective opiate receptor antagonist, were compared using paired positron emission tomography studies in two normal volunteers. Kinetics of total radioactivity (counts/mCi/pixel) was greater for [11C]diprenorphine than [11C]carfentanil in all regions. [11C]Carfentanil binding (expressed as the total/nonspecific ratio) reached near equilibrium at approximately 40 min, whereas [11C]diprenorphine showed a linear increase until approximately 60 min. Kinetics of specific binding demonstrated significant dissociation of [11C]carfentanil from opiate receptors, whereas little dissociation of [11C]diprenorphine was observed during the 90-min scan session. Regional distributions of [11C]carfentanil and [11C]diprenorphine were qualitatively and quantitatively different: Relative to the thalamus (a region with known predominance of mu-receptors), [11C]diprenorphine displayed greater binding in the striatum and cingulate and frontal cortex compared to [11C]carfentanil, consistent with labeling of additional, non-mu sites by [11C]diprenorphine. We conclude from these studies that [11C]diprenorphine labels other opiate receptor subtypes in addition to the mu sites selectively labeled by [11C]carfentanil. The nonselective nature of diprenorphine potentially limits its usefulness in defining abnormalities of specific opiate receptor subtypes in various diseases. Development of selective tracers for the delta- and kappa-opiate receptor sites, or alternatively use of unlabeled inhibitors to differentially displace mu, delta, and kappa subtypes, will help offset these limitations.

Measurement of benzodiazepine receptor number and affinity in humans using tracer kinetic modeling, positron emission tomography, and [11C]flumazenil.

Kinetic methods were used to obtain regional estimates of benzodiazepine receptor concentration (Bmax) and equilibrium dissociation constant (Kd) from high and low specific activity (SA) [11C]flumazenil ([11C] Ro 15-1788) positron emission tomography studies of five normal volunteers. The high and low SA data were simultaneously fit to linear and nonlinear three-compartment models, respectively. An additional inhibition study (pretreatment with 0.15 mg/kg of flumazenil) was performed on one of the volunteers, which resulted in an average gray matter K1/k2 estimate of 0.68 +/- 0.08 ml/ml (linear three-compartment model, nine brain regions). The free fraction of flumazenil in plasma (f1) was determined for each study (high SA f1: 0.50 +/- 0.03; low SA f1: 0.48 +/- 0.05). The free fraction in brain (f2) was calculated using the inhibition K1/k2 ratio and each volunteer's mean f1 value (f2 across volunteers = 0.72 +/- 0.03 ml/ml). Three methods (Methods I-III) were examined. Method I determined five kinetic parameters simultaneously [K1, k2, k3 (= konf2Bmax), k4, and konf2/SA] with no priori constraints. An average kon value of 0.030 +/- 0.003 nM-1 min-1 was estimated for receptor-rich regions using Method I. In Methods II and III, the konf2/SA parameter was specifically constrained using the Method I value of kon and the volunteer's values of f2 and low SA (Ci/mumol). Four parameters were determined simultaneously using Method II. In Method III, K1/k2 was fixed to the inhibition value and only three parameters were estimated. Method I provided the most variable results and convergence problems for regions with low receptor binding. Method II provided results that were less variable but very similar to the Method I results, without convergence problems. However, the K1/k2 ratios obtained by Method II ranged from 1.07 in the occipital cortex to 0.61 in the thalamus. Fixing the K1/k2 ratio in Method III provided a method that was physiologically consistent with the fixed value of f2 and resulted in parameters with considerably lower variability. The average Bmax values obtained using Method III were 100 +/- 25 nM in the occipital cortex, 64 +/- 18 nM in the cerebellum, and 38 +/- 5.5 nM in the thalamus; the average Kd was 8.9 +/- 1.0 nM (five brain regions).

Multicompartmental analysis of [11C]-carfentanil binding to opiate receptors in humans measured by positron emission tomography.

[11C]-Carfentanil is a high affinity opiate agonist that can be used to localize mu opiate receptors in humans by positron emission tomography (PET). A four-compartment model was used to obtain quantitative estimates of rate constants for receptor association and dissociation. PET studies were performed in five normal subjects in the absence and presence of 1 mg/kg naloxone. Arterial plasma concentration of [11C]-carfentanil and its labeled metabolites were determined during each PET study. The value of k3/k4 = Bmax/kD was determined for each subject in the presence and absence of naloxone. There was a significant reduction in the value of k3/k4 from 3.4 +/- 0.92 to 0.26 +/- 0.13 in the thalamus (p less than 0.01) and from 1.8 +/- 0.33 to 0.16 +/- 0.065 in the frontal cortex (p less than 0.001). Mean values of frontal cortex/occipital cortex and thalamus/occipital cortex ratios were determined for the interval 35-70 min after injection when receptor binding is high relative to nonspecific binding. The relationship between the measured region/occipital cortex values and the corresponding values of k3/k4 in the presence and absence of naloxone was: regions/occipital cortex = 0.95 + 0.74 (k3/k4) with r = 0.98 (n = 20). Simulation studies also demonstrated a linear relationship between the thalamus/occipital cortex or frontal cortex/occipital cortex ratio and k3/k4 for less than twofold increases or decreases in k3/k4. Simulation studies in which thalamic blood flow was varied demonstrated no significant effect on the region/occipital cortex ratio at 35-70 min for a twofold increase or fourfold decrease in blood flow. Therefore, the region/occipital cortex ratio can be used to quantitate changes in k3/k4 when tracer kinetic modeling is not feasible.

Quantification of human opiate receptor concentration and affinity using high and low specific activity [11C]diprenorphine and positron emission tomography.

[11C]Diprenorphine, a weak partial opiate agonist, and positron emission tomography were used to obtain noninvasive regional estimates of opiate receptor concentration (Bmax) and affinity (Kd) in human brain. Different compartmental models and fitting strategies were compared statistically to establish the most reliable method of parameter estimation. Paired studies were performed in six normal subjects using high (769-5,920 Ci/mmol) and low (27-80 Ci/mmol) specific activity (SA) [11C]diprenorphine. Two subjects were studied a third time using high SA [11C]diprenorphine after a pretreatment with 1-1.5 mg/kg of the opiate antagonist naloxone. After the plasma radioactivity was corrected for metabolites, the brain data were analyzed using a three-compartment model and nonlinear least-squares curve fitting. Linear differential equations were used to describe the high SA (low receptor occupancy) kinetics. The k3/k4 ratio varied from 1.0 +/- 0.2 (occipital cortex) to 8.6 +/- 1.6 (thalamus). Nonlinear differential equations were used to describe the low SA (high receptor occupancy) kinetics and the curve fits provided the konf2 product. The measured free fraction of [11C]diprenorphine in plasma (f1) was 0.30 +/- 0.03, the average K1/k2 ratio from the two naloxone studies was 1.1 +/- 0.2, and the calculated free fraction of [11C]diprenorphine in the brain (f2) was 0.3. Using the paired SA studies, the estimated kinetic parameters, and f2, separate estimates of Bmax and Kd were obtained. Bmax varied from 2.3 +/- 0.5 (occipital cortex) to 20.6 +/- 7.3 (cingulate cortex) nM. The average Kd (eight brain regions) was 0.85 +/- 0.17 nM.

Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression.

OBJECTIVE: Depression is commonly associated with frontal hypometabolic activity accompanied by hypermetabolism in certain limbic regions. It is unclear whether successful antidepressant treatments reverse these abnormalities or create new resting levels of metabolism. The aim of the present study was to assess the effects of successful paroxetine treatment on regional glucose metabolism in patients with major depression. METHOD: Positron emission tomography with [(18)F]fluorodeoxyglucose was performed on 13 male patients before and after 6 weeks of paroxetine therapy. Resting state scans were also acquired under similar conditions in 24 healthy male subjects for comparison. RESULTS: After successful paroxetine therapy, increased glucose metabolism occurred in dorsolateral, ventrolateral, and medial aspects of the prefrontal cortex (left greater than right), parietal cortex, and dorsal anterior cingulate. Areas of decreased metabolism were noted in both anterior and posterior insular regions (left) as well as right hippocampal and parahippocampal regions. In comparison to metabolism levels in a group of healthy volunteers, the increase in prefrontal metabolic activity represented a normalization of previously reduced metabolic activity, whereas the reduction in pregenual anterior cingulate activity represented a decrease from previously elevated metabolic levels. CONCLUSIONS: These results provide further support for a dysfunction in cortical-limbic circuitry in depression, which is at least partly reversed after successful paroxetine treatment.

PET imaging of cortical S2 serotonin receptors after stroke: lateralized changes and relationship to depression.

Patients with right-hemisphere strokes (N = 9) more than 1 year after injury had greater cortical binding of (3-N-[11C]methyl)spiperone than a similar group of patients with left-hemisphere strokes (N = 8) or normal control subjects (N = 17). The higher S2 serotonin receptor binding occurred in uninjured regions of the right parietal and temporal cortex. The ratio of binding in the ipsilateral to contralateral cortex showed a significant negative correlation with severity of depression scores in the left temporal cortex. These findings suggest that the biochemical response of the brain may be different depending on which hemisphere is injured and that some depressions may be a consequence of the failure to upregulate serotonin receptors after stroke.

Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness.

OBJECTIVE: Theories of human behavior from Plato to Freud have repeatedly emphasized links between emotion and reason, a relationship now commonly attributed to pathways connecting phylogenetically "old" and "new" brain regions. Expanding on this theory, this study examined functional interactions between specific limbic and neocortical regions accompanying normal and disease-associated shifts in negative mood state. METHOD: Regions of concordant functional change accompanying provocation of transient sadness in healthy volunteers and resolution of chronic dysphoric symptoms in depressed patients were examined with two positron emission tomography techniques: [15O]water and [18F]fluorodeoxyglucose, respectively. RESULTS: With sadness, increases in limbic-paralimbic blood flow (subgenual cingulate, anterior insula) and decreases in neocortical regions (right dorsolateral prefrontal, inferior parietal) were identified. With recovery from depression, the reverse pattern, involving the same regions, was seen--limbic metabolic decreases and neocortical increases. A significant inverse correlation between subgenual cingulate and right dorsolateral prefrontal activity was also demonstrated in both conditions. CONCLUSIONS: Reciprocal changes involving subgenual cingulate and right prefrontal cortex occur with both transient and chronic changes in negative mood. The presence and maintenance of functional reciprocity between these regions with shifts in mood in either direction suggests that these regional interactions are obligatory and probably mediate the well-recognized relationships between mood and attention seen in both normal and pathological conditions. The bidirectional nature of this limbic-cortical reciprocity provides additional evidence of potential mechanisms mediating cognitive ("top-down"), pharmacological (mixed), and surgical ("bottom-up") treatments of mood disorders such as depression.

The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study.

OBJECTIVE: In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients. METHOD: After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects. RESULTS: 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found. CONCLUSIONS: 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.

Paralimbic frontal lobe hypometabolism in depression associated with Huntington's disease.

We measured regional cerebral glucose metabolism using 2-[18F]-fluoro-2-deoxy-D-glucose and positron emission tomography in depressed and nondepressed patients with early Huntington's disease (HD), compared with appropriately matched controls. Caudate, putamen, and cingulate metabolism was significantly lower in patients with HD than in control subjects, independent of mood state. Orbital frontal-inferior prefrontal cortex hypometabolism, however, differentiated depressed patients from both nondepressed patients and normal controls. These findings implicate selective dysfunction of the paralimbic regions of the frontal lobes in the mood disorder of HD. The metabolic pattern is similar to that in depression associated with Parkinson's disease, suggesting that the integrity of pathways linking paralimbic frontal cortex and the basal ganglia may be integral to the normal regulation of mood.

Regional hypometabolism in Alzheimer's disease as measured by positron emission tomography after correction for effects of partial volume averaging.

Measurements of cerebral metabolism in patients with Alzheimer's disease (AD) using PET are artifactually depressed due to partial volume averaging of brain tissue activity with enlarged CSF spaces. To investigate the effects of correction for the expansion of CSF spaces on regional metabolic measures, as well as the correlations between neuropsychological test results and resting cerebral metabolism before and after partial volume correction, we applied an MRI-based method of partial volume correction to 18F-fluorodeoxyglucose (FDG)-PET data from eight patients diagnosed with probable AD and ten healthy elderly individuals. Before correction, the AD group had significantly lower cortex-to-cerebellum ratios in the posterior temporal, parietal, and frontal lobes in comparison to the control subjects. Partial volume correction of PET data resulted in 19 to 49% increases in regional activity in the AD group and 16 to 38% increases in the control group. The patients' persistence of significant hypometabolism in the frontal, posterior temporal, and parietal regions after partial volume correction suggests that a true reduction in regional cerebral glucose metabolism occurs in AD, even though its magnitude is a result of both metabolic reductions and the effects of atrophy. Partial volume correction of PET data in the AD group had a significant impact on the correlations between regional glucose metabolism and neuropsychological performance. These findings suggest that accounting for differential extent and distribution of cerebral atrophy in patients with AD and in healthy individuals may potentially improve our ability to interpret specific cognitive dysfunction in the context of the functional imaging data.

SPECT perfusion imaging in the diagnosis of Alzheimer's disease: a clinical-pathologic study.

OBJECTIVE: Numerous studies have suggested that temporoparietal hypoperfusion seen on brain imaging with SPECT may be useful in diagnosing AD during life. However, these studies have often been limited by lack of pathologic validation and unrepresentative samples. The authors performed this study to determine whether SPECT imaging provides diagnostically useful information in addition to that obtained from a clinical examination. METHODS: Clinical data and SPECT images were collected prospectively, and patients were followed to autopsy. Clinical history, pathologic findings, and SPECT images were each evaluated by raters blind to other features, and clinical and SPECT diagnoses were compared with pathologic diagnoses. The study population consisted of 70 patients with dementia, followed to autopsy; 14 controls followed to autopsy; and 71 controls (no autopsy performed). The primary outcome was the likelihood of a pathologic diagnosis of AD given a positive clinical diagnosis, a positive SPECT diagnosis, and both. RESULTS: When all participants (patients and controls) were included in the analysis, the clinical diagnosis of "probable" AD was associated with an 84% likelihood of pathologic AD. A positive SPECT scan raised the likelihood of AD to 92%, whereas a negative SPECT scan lowered the likelihood to 70%. SPECT was more useful when the clinical diagnosis was "possible" AD, with the likelihood of 67% without SPECT, 84% with a positive SPECT, and 52% with a negative SPECT. Similar results were found when only patients with dementia were included in the analysis. CONCLUSIONS: In the evaluation of dementia, SPECT imaging can provide clinically useful information indicating the presence of AD in addition to the information that is obtained from clinical evaluation.

An ERP study of the temporal course of the Stroop color-word interference effect.

The electrophysiological correlates of the Stroop color-word interference effect were studied in eight healthy subjects using high-density Event-Related Potentials (ERPs). Three response modalities were compared: Overt Verbal, Covert Verbal, and Manual. Both Overt Verbal and Manual versions of the Stroop yielded robust Stroop color-word interference as indexed by longer RT for incongruent than congruent color words. The Incongruent vs Congruent ERP difference wave presented two effects. A first effect was a medial dorsal negativity between 350-500 ms post-stimulus (peak at 410 ms). This effect had a significantly different scalp distribution in the Verbal and Manual Stroop versions, with an anterior-medial focus for overt or covert speech, and a broader medial-dorsal distribution for the manual task. Dipole source analysis suggested two independent generators in anterior cingulate cortex. Later on in time, a prolonged positivity developed between 500-800 ms post-stimulus over left superior temporo-parietal scalp. This effect was present for all the three response modalities. A possible interpretation of these results is that Stroop color-word interference first activates anterior cingulate cortex (350-500 ms post-stimulus), followed by activation of the left temporo-parietal cortex, possibly related to the need of additional processing of word meaning.

Paralimbic hypoperfusion in unipolar depression.

METHODS: Relative regional cerebral blood flow was measured with SPECT using 99mTc-hexamethylpropyleneamine oxime in 13 patients with severe unipolar depression that was nonresponsive to drug therapy and 11 age-matched nondepressed controls. RESULTS: All patients were clinically depressed and taking antidepressant drugs at the time of the study. The relative blood flow was significantly decreased bilaterally in the frontal cortex, anterior temporal cortex, anterior cingulate gyrus and caudate in the depressed patients compared with the nondepressed healthy controls. The greatest decreases were seen in the paralimbic regions, specifically, the inferior frontal and cingulate cortex. No significant changes were seen in the parietal cortex, occipital cortex or thalami. Psychiatric rating scales correlated poorly with regional blood flow, except for the degree of psychomotor slowing, which was negatively correlated with frontal and cingulate perfusion. CONCLUSION: These findings implicate selective dysfunction of paralimbic brain regions in clinically depressed patients, independent of their medication use, and support the concept of specific neural systems that regulate mood. Recognition of these regional abnormalities may have clinical utility in both the diagnosis and treatment of depression.