Neuroanatomical Correlates of a Lactate-Induced Anxiety Attack

Reiman, Eric M.; Raichle, Marcus E.; Robins, Eli; Mintun, Mark A.; Fusselman, Maureen J.; Fox, Peter T.; Price, Joseph L.; Hackman, Kathryn A.

doi:10.1001/archpsyc.1989.01810060013003

Cited by 313 publications

(121 citation statements)

References 32 publications

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“…In similar clinical groups, Reiman et al (41) studied regional CBF by using PET and found no changes in regional CBF during lactate infusion in either normal controls or nonpanicking patients, whereas, during panic attacks, CBF was significantly increased bilaterally in several brain areas. Interpretation of these results and comparison with observations in our study is difficult, because, in their studies (40,41), the CBF measurements during lactate infusion were obtained in the resting state only; lactate was continuously infused for 20-30 min rather than given as bolus; total dose of lactate injected was 4-to 5-fold higher than in our study; and no measurements of plasma lactate, pyruvate, and the lactate͞ pyruvate ratios were reported. It is of interest that, among other theories, changes in the redox state (lactate͞pyruvate ratio) in the brain cells were suggested to be involved in the development of panic attacks (42).…”

Section: Discussionmentioning

confidence: 99%

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Mintun

Vlassenko

Rundle

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

132

104

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The factors regulating cerebral blood flow (CBF) changes in physiological activation remain the subject of great interest and debate. Recent experimental studies suggest that an increase in cytosolic NADH mediates increased blood flow in the working brain. Lactate injection should elevate NADH levels by increasing the lactate͞ pyruvate ratio, which is in near equilibrium with the NADH͞NAD ؉ ratio. We studied CBF responses to bolus lactate injection at rest and in visual stimulation by using positron-emission tomography in seven healthy volunteers. Bolus lactate injection augmented the CBF response to visual stimulation by 38 -53% in regions of the visual cortex but had no effect on the resting CBF or the wholebrain CBF. These lactate-induced CBF increases correlated with elevations in plasma lactate͞pyruvate ratios and in plasma lactate levels but not with plasma pyruvate levels. Our observations support the hypothesis that an increase in the NADH͞NAD ؉ ratio activates signaling pathways to selectively increase CBF in the physiologically stimulated brain regions.T he nature of the link between cerebral blood flow (CBF) and energy metabolism is of great interest and importance but remains controversial despite decades of research and debate. Although CBF augmentation is still considered to be a hallmark of intensified neural activity, previous assumptions that behaviorally induced increases in local blood flow reflect similar local increases in oxidative metabolism (1) have been contradicted by brain imaging studies with positron-emission tomography (PET) (2, 3) and functional MRI (4). Fox and his colleagues (2, 3) demonstrated that in normal, awake adult humans, stimulation of the visual or somatosensory cortex results in dramatic increases in CBF but minimal increases in oxygen consumption. Increases in glucose utilization are similar to changes in CBF (3, 5). Although it is often assumed that the increase in CBF in neural activation is driven by a need for increased delivery of oxygen or glucose, it has been demonstrated in human subjects that the CBF response to physiological activation is not altered by either stepped hypoglycemia (6) or hypoxia (7). These results suggest that increased CBF during physiological brain activation does not occur to prevent a shortage of these metabolic substrates. Ido et al. (8) recently reported that CBF in activated rat brain is modified by changes in the plasma lactate͞pyruvate ratio: CBF was augmented when lactate͞pyruvate ratios were raised and attenuated when the ratios were lowered. Specifically, immediately after lactate bolus injection, the magnitude of the CBF increase associated with sensory stimulation approximately doubled. Based on the near equilibrium between the ratios of lactate͞pyruvate and cytosolic free NADH͞NAD ϩ (which reflects the local environment redox state) (9), they suggested that cytosolic free NADH is an important trigger or sensor of blood flow. The reoxidation of NADH to NAD ϩ is a step of vital importance for brain cells, especially in the acti...

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Section: Discussionmentioning

confidence: 99%

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Mintun

Vlassenko

Rundle

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

132

104

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“…The insula is involved in gustatory, visceral sensation and visceral motor responses, but also in psychosomatic functions with autonomic regulation and emotion processing (see Damasio et al, 2000, Ketter et al,1996, Reiman et al, 1989Lane et al, 1997;Ottowitz et al, 2004; for an overview, see Nagai et al, 2007). Mayberg et al (1999) and Kennedy et al (2001) found post-treatment responsiveness associated with decreased metabolism in the insula.…”

Section: Discussionmentioning

confidence: 99%

Brain activation predicts treatment improvement in patients with major depressive disorder

Samson

Meisenzahl

Scheuerecker

et al. 2011

Journal of Psychiatric Research

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a b s t r a c tMajor depressive disorder (MDD) is associated with alterations in brain function that might be useful for therapy evaluation. The current study aimed to identify predictors for therapy improvement and to track functional brain changes during therapy. Twenty-one drug-free patients with MDD underwent functional MRI twice during performance of an emotional perception task: once before and once after 4 weeks of antidepressant treatment (mirtazapine or venlafaxine). Twelve healthy controls were investigated once with the same methods. A significant difference between groups was a relative greater activation of the right dorsolateral prefrontal cortex (dlPFC) in the patients vs. controls. Before treatment, patients responding better to pharmacological treatment showed greater activation in the dorsomedial PFC (dmPFC), posterior cingulate cortex (pCC) and superior frontal gyrus (SFG) when viewing of negative emotional pictures was compared with the resting condition. Activations in the caudate nucleus and insula contrasted for emotional compared to neutral stimuli were also associated with successful treatment. Responders had also significantly higher levels of activation, compared to non-responders, in a range of other brain regions. Brain activation related to treatment success might be related to altered self-referential processes and a differential response to external emotional stimuli, suggesting differences in the processing of emotionally salient stimuli between those who are likely to respond to pharmacological treatment and those who will not. The present investigation suggests the pCC, dmPFC, SFG, caudate nucleus and insula may have a key role as a biological marker for treatment response and predictor for therapeutic success.

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“…Deactivation of the parahippocampal region in healthy volunteers has been reported after panic attacks induced by lactate (Reiman et al, 1989) and CCK-4 (Javanmard et al, 1999), and with anxiety induced by presentation of combat-related images (Bremner et al, 1999b) and autobiographical memory scripts (Liotti et al, 2000). In addition, the abnormal asymmetry of resting activity in the parahippocampal gyri has been associated with panic disorder and with vulnerability to lactateinduced panic (Reiman et al, 1984(Reiman et al, , 1986Nordahl et al, 1990Nordahl et al, , 1998Bisaga et al, 1998;De Cristofaro et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Effects of Cannabidiol (CBD) on Regional Cerebral Blood Flow

Crippa

Zuardi

Garrido

et al. 2003

Neuropsychopharmacol

257

224

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Animal and human studies have suggested that cannabidiol (CBD) may possess anxiolytic properties, but how these effects are mediated centrally is unknown. The aim of the present study was to investigate this using functional neuroimaging. Regional cerebral blood flow (rCBF) was measured at rest using 99m Tc-ECD SPECT in 10 healthy male volunteers, randomly divided into two groups of five subjects. Each subject was studied on two occasions, 1 week apart. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. SPECT images were acquired 90 min after drug ingestion. The Visual Analogue Mood Scale was applied to assess subjective states. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping (SPM). CBD significantly decreased subjective anxiety and increased mental sedation, while placebo did not induce significant changes. Assessment of brain regions where anxiolytic effects of CBD were predicted a priori revealed two voxel clusters of significantly decreased ECD uptake in the CBD relative to the placebo condition (po0.001, uncorrected for multiple comparisons). These included a medial temporal cluster encompassing the left amygdala-hippocampal complex, extending into the hypothalamus, and a second cluster in the left posterior cingulate gyrus. There was also a cluster of greater activity with CBD than placebo in the left parahippocampal gyrus (po0.001). These results suggest that CBD has anxiolytic properties, and that these effects are mediated by an action on limbic and paralimbic brain areas.

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Neuroanatomical Correlates of a Lactate-Induced Anxiety Attack

Cited by 313 publications

References 32 publications

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Brain activation predicts treatment improvement in patients with major depressive disorder

Effects of Cannabidiol (CBD) on Regional Cerebral Blood Flow

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