Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder.

Inflammation-related changes in the concentrations of kynurenine-pathway metabolites occur in depression secondary to medical conditions but have not been well characterized in primary bipolar disorder (BD), with contradictory results potentially attributable to the presence or absence of psychosis and/or medication effects. In contrast, reductions in hippocampal and amygdalar volume that theoretically reflect dendritic atrophy occurring in the context of a neurotoxic process are commonly reported in unmedicated BD patients. Here we tested whether the concentrations of putatively neuroprotective (kynurenic acid, KynA) and neurotoxic (3-hydroxy-kynurenine, 3HK and quinolinic acid, QA) kynurenine-pathway metabolites were altered in primary BD and whether these metabolites were associated with hippocampal and amygdalar volume. Twenty-five moderately-to-severely depressed unmedicated subjects and 38 moderately-to-severely depressed medicated subjects who met DSM-IV-TR criteria for BD, as well as 48 healthy controls (HCs) completed a structural MRI scan and provided a blood sample for kynurenine metabolite analysis, performed using high performance liquid chromatography with tandem mass spectrometry. Gray matter volumes were measured with the automated segmentation software, FreeSurfer. A putative neuroprotective index, KynA/QA, was significantly lower in the BD subjects relative to the HCs, a finding that was unrelated to current treatment with medication or a prior history of psychosis. Further, another putative neuroprotective index, KynA/3HK was positively associated with hippocampal volume in the BD group after controlling for age, sex, body mass index (BMI), and intracranial volume (ICV). Kyn/3HK was significantly associated with total amygdalar volume in the BD group, but after controlling for age, sex, BMI, but not ICV, this association was reduced to a trend. In addition, Kyn/3HK was positively associated with amygdalar volume in the HCs although the association was no longer significant after accounting for the effects of age, sex, and BMI. The results raise the possibility that BD-associated abnormalities in kynurenine metabolism may impact the structure of the hippocampus and amygdala, highlighting a pathway through which inflammation may exert neuropathological effects in the context of depression.

Neurophysiological correlates of autobiographical memory deficits in currently and formerly depressed subjects.

BACKGROUND: Individuals with major depressive disorder (MDD) tested in either the depressed (dMDD) or remitted phase (rMDD) recall fewer specific and more categorical autobiographical memories (AMs) compared to healthy controls (HCs). The current study aimed to replicate findings of AM overgenerality in dMDD or rMDD, and to elucidate differences in neurophysiological correlates of AM recall between these MDD samples and HCs. METHOD: Unmedicated participants who met criteria for the dMDD, rMDD or HC groups (n = 16/group) underwent functional magnetic resonance imaging (fMRI) while recalling AMs in response to emotionally valenced cue words. Control tasks involved generating examples from an assigned semantic category and counting the number of risers in a letter string. RESULTS: The results showed fewer specific and more categorical AMs in both MDD samples versus HCs; dMDDs and rMDDs performed similarly on these measures. The neuroimaging results showed differences between groups in the dorsomedial prefrontal cortex (DMPFC), lateral orbitofrontal cortex (OFC), anterior insula, inferior temporal gyrus and parahippocampus/hippocampus during specific AM recall versus example generation. During specific AM recall cued by positively valenced words, group differences were evident in the DMPFC, middle temporal gyrus, parahippocampus/hippocampus and occipital gyrus, whereas differences during specific AM recall cued by negatively valenced words were evident in the DMPFC, superior temporal gyrus and hippocampus. CONCLUSIONS: AM deficits exist in rMDDs, suggesting that these impairments constitute trait-like abnormalities in MDD. We also found distinct patterns of hemodynamic activity for each group as they recalled specific AMs, raising the possibility that each group used a partly unique strategy for self-referential focus during successful retrieval of specific memories.

Understanding neural system dynamics through task modulation and measurement of functional MRI amplitude, latency, and width.

Estimates of hemodynamic amplitude, delay, and width were combined to investigate system dynamics involved in lexical decision making. Subjects performed a lexical decision task using word and nonword stimuli rotated 0 degrees, 60 degrees, or 120 degrees. Averaged hemodynamic responses to repeated stimulation were fit to a Gamma-variate function convolved with a heavyside function of varying onset and duration to estimate each voxel's activation delay and width. Consistent with prolonged reaction times for the rotated stimuli and nonwords, the motor cortex showed delayed hemodynamic onset for both conditions. Language areas such as the lingual gyrus, middle temporal gyrus, fusiform gyrus, and precuneus all showed delayed hemodynamic onsets to rotated stimuli but not to nonword stimuli. The inferior frontal gyrus showed both increased onset latency for rotated stimuli and a wider hemodynamic response to nonwords, consistent with prolonged processing in this area during the lexical decision task. Phonological processing areas such as superior temporal and angular gyrus showed no delay or width difference for rotated stimuli. These results suggest that phonological routes but not semantic routes to the lexicon can proceed regardless of stimulus orientation. This study demonstrates the utility of estimating hemodynamic delay and width in addition to amplitude allowing for more quantitative measures of brain function such as mental chronometry.

Human temporal lobe activation by speech and nonspeech sounds.

Functional organization of the lateral temporal cortex in humans is not well understood. We recorded blood oxygenation signals from the temporal lobes of normal volunteers using functional magnetic resonance imaging during stimulation with unstructured noise, frequency-modulated (FM) tones, reversed speech, pseudowords and words. For all conditions, subjects performed a material-nonspecific detection response when a train of stimuli began or ceased. Dorsal areas surrounding Heschl's gyrus bilaterally, particularly the planum temporale and dorsolateral superior temporal gyrus, were more strongly activated by FM tones than by noise, suggesting a role in processing simple temporally encoded auditory information. Distinct from these dorsolateral areas, regions centered in the superior temporal sulcus bilaterally were more activated by speech stimuli than by FM tones. Identical results were obtained in this region using words, pseudowords and reversed speech, suggesting that the speech-tones activation difference is due to acoustic rather than linguistic factors. In contrast, previous comparisons between word and nonword speech sounds showed left-lateralized activation differences in more ventral temporal and temporoparietal regions that are likely involved in processing lexical-semantic or syntactic information associated with words. The results indicate functional subdivision of the human lateral temporal cortex and provide a preliminary framework for understanding the cortical processing of speech sounds.

Language dominance in neurologically normal and epilepsy subjects: a functional MRI study.

Language dominance and factors that influence language lateralization were investigated in right-handed, neurologically normal subjects (n = 100) and right-handed epilepsy patients (n = 50) using functional MRI. Increases in blood oxygenation-dependent signal during a semantic language activation task relative to a non-linguistic, auditory discrimination task provided an index of language system lateralization. As expected, the majority of both groups showed left hemisphere dominance, although a continuum of activation asymmetry was evident, with nearly all subjects showing some degree of right hemisphere activation. Using a categorical dominance classification, 94% of the normal subjects were considered left hemisphere dominant and 6% had bilateral, roughly symmetric language representation. None of the normal subjects had rightward dominance. There was greater variability of language dominance in the epilepsy group, with 78% showing left hemisphere dominance, 16% showing a symmetric pattern and 6% showing right hemisphere dominance. Atypical language dominance in the epilepsy group was associated with an earlier age of brain injury and with weaker right hand dominance. Language lateralization in the normal group was weakly related to age, but was not significantly related to sex, education, task performance or familial left-handedness.

Language processing is strongly left lateralized in both sexes. Evidence from functional MRI.

Functional MRI (fMRI) was used to examine gender effects on brain activation during a language comprehension task. A large number of subjects (50 women and 50 men) was studied to maximize the statistical power to detect subtle differences between the sexes. To estimate the specificity of findings related to sex differences, parallel analyses were performed on two groups of randomly assigned subjects. Men and women showed very similar, strongly left lateralized activation patterns. Voxel-wise tests for group differences in overall activation patterns demonstrated no significant differences between women and men. In further analyses, group differences were examined by region of interest and by hemisphere. No differences were found between the sexes in lateralization of activity in any region of interest or in intrahemispheric cortical activation patterns. These data argue against substantive differences between men and women in the large-scale neural organization of language processes.

Conceptual processing during the conscious resting state. A functional MRI study.

Localized, task-induced decreases in cerebral blood flow are a frequent finding in functional brain imaging research but remain poorly understood. One account of these phenomena postulates processes ongoing during conscious, resting states that are interrupted or inhibited by task performance. Psychological evidence suggests that conscious humans are engaged almost continuously in adaptive processes involving semantic knowledge retrieval, representation in awareness, and directed manipulation of represented knowledge for organization, problem-solving, and planning. If interruption of such 'conceptual' processes accounts for task-induced deactivation, tasks that also engage these conceptual processes should not cause deactivation. Furthermore, comparisons between conceptual and nonconceptual tasks should show activation during conceptual tasks of the same brain areas that are 'deactivated' relative to rest. To test this model, functional magnetic resonance imaging data were acquired during a resting state, a perceptual task, and a semantic retrieval task. A network of left-hemisphere polymodal cortical regions showed higher signal values during the resting state than during the perceptual task but equal values during the resting and semantic conditions. This result is consistent with the proposal that perceptual tasks interrupt processes ongoing during rest that involve many of the same brain areas engaged during semantic retrieval. As further evidence for this model, the same network of brain areas was activated in two direct comparisons between semantic and perceptual processing tasks. This same 'conceptual processing' network was also identified in several previous studies that contrasted semantic and perceptual tasks or resting and active states. The model proposed here offers a unified account of these findings and may help to explain several unanticipated results from prior studies of semantic processing.

Side of seizure focus predicts left medial temporal lobe activation during verbal encoding.

OBJECTIVE: Functional MRI (FMRI) was used to investigate the effect of medial temporal lobe (MTL) pathology on activation of language encoding areas in patients with temporal lobe epilepsy (TLE). METHODS: Whole-brain FMRI was obtained. Twenty-eight patients with either left TLE (LTLE) or right TLE (RTLE) performed a semantic decision task alternating with an auditory perceptual task. RESULTS: Activation of language areas in the frontal and parietal lobes was similar in both groups, with no group differences in the total number of active voxels. However, the RTLE group showed much stronger activation of the left MTL, including the hippocampus, parahippocampal gyrus, and collateral sulcus, than did the LTLE group. CONCLUSIONS: Activation of the left MTL during semantic encoding discriminates patients with RTLE and LTLE. This FMRI technique may potentially be of use in determining memory lateralization and for predicting the side of seizure focus in TLE.

The role of mu and kappa opioid receptors within the periaqueductal gray in the expression of conditional hypoalgesia.

The periaqueductal gray (PAG) is a midbrain structure involved in the modulation of pain and expression of classically conditioned fear responses. Non-selective opioid antagonists applied to the PAG block the expression of hypoalgesia in rats exposed to a Pavlovian signal for shock. This study was conducted to determine the anatomical and pharmacological specificity of the PAG's role in conditional hypoalgesia. Rat subjects received injections of either the mu opioid antagonist CTAP (6.6 nMol), the kappa opioid antagonist Nor-binaltorphimine (Nor-BNI, 6.6 nMol) or saline. Injections were made into either the dorsolateral (dlPAG) or ventrolateral (vlPAG) PAG prior to the presentation of an auditory stimulus that had previously been paired with foot shock while measuring nociception with the radiant heat tail flick (TF) test. Elevation in TF latency in response to the auditory stimulus was blocked only by administration of CTAP into the vlPAG. These results suggest that conditional hypoalgesia (CHA) is subserved by mu but not kappa opioid receptors located in the vlPAG but not the dlPAG.

Antinociception following opioid stimulation of the basolateral amygdala is expressed through the periaqueductal gray and rostral ventromedial medulla.

The amygdala, periaqueductal gray (PAG), and rostral ventromedial medulla (RVM) are critical for the expression of some forms of stress-related changes in pain sensitivity. In barbiturate anesthetized rats, microinjection of agonists for the mu opioid receptor into the amygdala results in inhibition of the tail flick (TF) reflex evoked by radiant heat. We tested the idea that TF inhibition following opioid stimulation of the amygdala is expressed through a serial circuit which includes the PAG and RVM. Rats were anesthetized and prepared for microinjection of DAMGO (0.5 microg/0.25 microl) into the basolateral amygdala (BLA) and lidocaine HCl (2.5%/0.4-0.5 microl) into either the ventrolateral PAG or RVM. Lidocaine did not significantly alter baseline values for TF latency or TF amplitude. When injected into the PAG prior to DAMGO application in the BLA, lidocaine significantly attenuated DAMGO-induced antinociception for the entire 40 min testing session. Similar treatment in the RVM also resulted in an attenuation of antinociception although rats showed significant recovery of TF inhibition by 40 min after lidocaine injection. Since acute injection of lidocaine into the RVM also affected baseline heart rate, separate animals were prepared with small electrolytic lesions placed in the RVM. Chronic RVM lesions also blocked TF inhibition produced by amygdala stimulation but did not affect heart rate. These results, when taken together with similar findings in awake behaving animals, suggest that a neural circuit which includes the amygdala, PAG, and RVM is responsible for the expression of several forms of hypoalgesia in the rat.

Neural systems for the expression of hypoalgesia during nonassociative fear.

A single brief exposure to moderately intense while noise is sufficient to produce opioid-mediated antinociception in rats. This form of stress-induced hypoalgesia represents a response to unconditional fear or anxiety. Three experiments compared the neural circuits responsible for learned versus unlearned fear responses. Male rats received lesions of the medial geniculate nucleus, lateral or central nuclei of the amygdala, or the ventral, dorsal lateral, or dorsal medial periaqueductal gray (PAG). Controls showed a pronounced elevation in tail-flick latency following presentation of 90-dB white noise. All lesions, with the exception of dorsolateral and dorsomedial PAG, significantly blocked this response. These results support the idea that hypoalgesia produced by aversive auditory stimuli uses a common neural circuit regardless of whether the response is a product of associative learning or unconditional fear/anxiety.

Microinfusion of mu but not delta or kappa opioid agonists into the basolateral amygdala results in inhibition of the tail flick reflex in pentobarbital-anesthetized rats.

Recent evidence suggests that certain forms of opioid-mediated hypoalgesia may depend on monosynaptic projections from the amygdala to nociceptive modulatory neurons in the midbrain. We recently demonstrated that the microinjection of morphine sulfate into the basolateral nucleus of the amygdala will result in a robust elevation of radiant heat tail flick (TF) latency in the pentobarbital-anesthetized rat. The present study was conducted to begin to clarify the opioid receptor type(s) responsible for this effect. Rats were anesthetized with sodium pentobarbital and prepared for microinfusion and TF testing. Rats received simultaneous bilateral infusions of agonists for mu ([D-Ala2, N-MePhe4, Gly-ol 5] enkephaphalin (DAMGO); 0.01, 0.05, 0.1, 1.0 or 5.0 micrograms), delta ([D-Pen2, D-Pen5]enkephalin [DPDPE]; 6.458 or 64.58 micrograms) or kappa (trans-3,4-dichloro-N-methyl-N-(2-(1-pyrolidinyl)-cyclohexyl)-benz ene acetamide methanesulfonate hydrate [U50, 488H]; 5.0, 40.0 or 84.0 micrograms) opioid receptors during TF testing. The mu agonist produced a dose- and time-dependent elevation in TF latency when injected into the basolateral amygdala. Application of the delta and kappa agonists to similar sites within the amygdala was without effect. In separate experiments, U50, 488H and DPDPE were injected into the lateral ventricle at concentrations similar to those applied to the amygdala. Intracerebroventricular administration of these compounds resulted in reliable inhibition of TF. These results indicate that mu opioid receptors in the basolateral amygdala may be able to modulate transmission in a recently identified neural circuit that is at least partially responsible for the expression of stress-related hypoalgesia in behaving animals.

Effects of muscimol applied to the basolateral amygdala on acquisition and expression of contextual fear conditioning in rats.

The amygdala is known to be important for normal aversive Pavlovian learning in the rat. The relative contribution of the amygdala to the learning vs. performance of conditional fear with the GABAa agonist muscimol was assessed. Rats were prepared with cannulas aimed at the basolateral amygdala and trained in a contextual fear conditioning paradigm in which each subject received a series of footshocks in a distinctive observation chamber. Conditional responses evoked after exposure to the observation chamber were assessed 24 hr later. Rats that were pretreated with muscimol before performance showed a significantly attenuated fear response, and injections made before acquisition resulted in a much smaller decrement in conditional fear measured 24 hr after training. These results indicate that acquisition-related processes that may be occurring within the amygdala are more difficult to disrupt than those associated with performance.

Hypoalgesia in response to sensitization during acute noise stress.

Three experiments examined the antinociceptive response shown by rats during exposure to loud noise. Noise exposure resulted in a time-dependent elevation of radiant heat tail flick latency that varied as a function of stimulus intensity. Noise stress hypoalgesia in response to a 90-dB stimulus was blocked by pretreatment with the opioid antagonist naltrexone (0.1-7.0 mg/kg). Systemic administration of midazolam (2 mg/kg) prior to exposure to the stressor attenuated the elevation in tail flick latency. Because topographically similar antinociceptive responses may be elicited with a low intensity noise stimulus that has served as a Pavlovian conditional stimulus for shock, the use of this paradigm may permit direct comparisons of associative and nonassociative fear responses using qualitatively similar auditory stimuli.

Lesions of the amygdala block conditional hypoalgesia on the tail flick test.

Exposure to an innocuous stimulus that has been paired with footshock during Pavlovian conditioning results in the activation of descending antinociceptive systems in the rat. Several recent studies indicate that the hypoalgesia observed when contextual stimuli are paired with shock and the formalin test is used to measure antinociception depends on the integrity of a neural circuit which includes the amygdala and the periaqueductal gray. The present experiment was designed to determine if the amygdala is also critical for hypoalgesia in response to a discrete auditory signal for footshock when hypoalgesia is measured with the radiant heat tail flick test. Groups of rats were exposed to a series of paired presentations of a tone and footshock or associative control treatments. After training, one half of the animals received large electrolytic lesions of the amygdala. Lesions of the amygdala blocked the time dependent elevation in tail flick latency following tone presentation in animals given paired training, but did not alter baseline tail flick responding. These data indicate that the amygdala is also essential for fear-related modulation of spinally mediated nociceptive reflexes, and provide further support for our current model in which amygdalo-mesencephalic projections are critical for the expression of certain forms of stress-induced hypoalgesia.

Inhibition of the tail flick reflex following microinjection of morphine into the amygdala.

Recent evidence indicates that the amygdala plays a critical role in the activation of brain stem antinociceptive systems during stress. In the present experiment, bilateral microinjection of morphine sulfate (10 micrograms) into the amygdala of pentobarbital-anesthetized rats resulted in a time-dependent elevation in latency of the tail flick reflex evoked by radiant heat. The most effective sites within the amygdala were in or immediately adjacent to the basolateral nucleus. The relative amplitude of the tail flick reflex did not differ as a function of repeated testing or morphine treatment. These results suggest that important forebrain inputs which normally activate endogenous antinociceptive systems in behaving animals may be manipulated and studied in detail using the anesthetized rat.