Richard J. Maddock

The retrosplenial cortex and emotion: new insights from functional neuroimaging of the human brain.

Little is known about the function of the retrosplenial cortex and until recently, there was no evidence that it had any involvement in emotional processes. Surprisingly, recent functional neuroimaging studies show that the retrosplenial cortex is consistently activated by emotionally salient words. A review of the functional neuroimaging literature reveals a previously overlooked pattern of observations: the retrosplenial cortex is the cortical region most consistently activated by emotionally salient stimuli. Evidence that this region is also involved in episodic memory suggests that it might have a role in the interaction between emotion and episodic memory. Recognition that the retrosplenial cortex has a prominent role in the processing of emotionally salient stimuli invites further studies to define its specific functions and its interactions with other emotion-related brain regions.

Posterior cingulate cortex activation by emotional words: fMRI evidence from a valence decision task

Functional imaging studies consistently find that emotional stimuli activate the posterior cingulate cortex, a region that appears to have memory‐related functions. However, prior imaging studies have not controlled for non‐emotional stimulus features that might activate this region by engaging memory processes unrelated to emotion. This study examined whether emotional words activated the posterior cingulate cortex when these potentially confounding factors were controlled. Sixty‐four pleasant and 64 unpleasant words were matched with neutral words on non‐emotional features known to influence memory. Eight subjects underwent block‐designed functional magnetic resonance imaging scans while evaluating the valence of these words. The posterior cingulate cortex was significantly activated bilaterally during both unpleasant and pleasant compared to neutral words. The strongest activation peak with both unpleasant and pleasant words was observed in the left subgenual cingulate cortex. Anteromedial orbital and left inferior and middle frontal cortices were also activated by both pleasant and unpleasant words. Right amygdala and auditory cortex were activated only by unpleasant words, while left frontal pole was activated only by pleasant words. The results show that activation of the posterior cingulate cortex by emotional stimuli cannot be attributed to the memory‐enhancing effects of non‐emotional stimulus features. The findings are consistent with the suggestion that this region may mediate interactions of emotional and memory‐related processes. The results also extend prior findings that evaluating emotional words consistently activates the subgenual cingulate cortex, and suggest a means of probing this region in patients with mood disorders. Hum. Brain Mapping 18:30–41, 2003.

REMEMBERING FAMILIAR PEOPLE: THE POSTERIOR CINGULATE CORTEX AND AUTOBIOGRAPHICAL MEMORY RETRIEVAL

Most functional imaging studies of memory retrieval investigate memory for standardized laboratory stimuli. However, naturally acquired autobiographical memories differ from memories of standardized stimuli in important ways. Neuroimaging studies of natural memories may reveal distinctive patterns of brain activation and may have particular value in assessing clinical disorders of memory. This study used functional magnetic resonance imaging to investigate brain activation during successful retrieval of autobiographical memories elicited by name-cued recall of family members and friends. The caudal part of the left posterior cingulate cortex was the most strongly activated region and was significantly activated in all eight subjects studied. Most subjects also showed significant activation of the left anterior orbitomedial, anterior middle frontal, precuneus, cuneus, and posterior inferior parietal cortices, and the right posterior cingulate and motor cortices.Our findings are consistent with prior studies showing posterior cingulate cortex activation during autobiographical memory retrieval. This region is also consistently activated during retrieval of standardized memory stimuli when experimental designs emphasizing successful retrieval are employed. Our results support the hypothesis that the posterior cingulate cortex plays an important role in successful memory retrieval. The posterior cingulate cortex has strong reciprocal connections with entorhinal and parahippocampal cortices. Studies of early Alzheimers disease, temporal lobectomy, and hypoxic amnesia show that hypometabolism of the posterior cingulate cortex is an early and prominent indicator of pathology in these patients. Our findings suggest that autobiographical memory retrieval tasks could be used to probe the functional status of the posterior cingulate cortex in patients with early Alzheimers disease or at risk for that condition.

GABA Concentration Is Reduced in Visual Cortex in Schizophrenia and Correlates with Orientation-Specific Surround Suppression

The neural mechanisms underlying cognitive deficits in schizophrenia remain essentially unknown. The GABA hypothesis proposes that reduced neuronal GABA concentration and neurotransmission results in cognitive impairments in schizophrenia. However, few in vivo studies have directly examined this hypothesis. We used magnetic resonance spectroscopy (MRS) at high field to measure visual cortical GABA levels in 13 subjects with schizophrenia and 13 demographically matched healthy control subjects. We found that the schizophrenia group had an ∼10% reduction in GABA concentration. We further tested the GABA hypothesis by examining the relationship between visual cortical GABA levels and orientation-specific surround suppression (OSSS), a behavioral measure of visual inhibition thought to be dependent on GABAergic synaptic transmission. Previous work has shown that subjects with schizophrenia exhibit reduced OSSS of contrast discrimination (Yoon et al., 2009). For subjects with both MRS and OSSS data (n = 16), we found a highly significant positive correlation (r = 0.76) between these variables. GABA concentration was not correlated with overall contrast discrimination performance for stimuli without a surround (r = −0.10). These results suggest that a neocortical GABA deficit in subjects with schizophrenia leads to impaired cortical inhibition and that GABAergic synaptic transmission in visual cortex plays a critical role in OSSS.

MR spectroscopic studies of the brain in psychiatric disorders

The measurement of brain metabolites with magnetic resonance spectroscopy (MRS) provides a unique perspective on the brain bases of neuropsychiatric disorders. As a context for interpreting MRS studies of neuropsychiatric disorders, we review the characteristic MRS signals, the metabolic dynamics,and the neurobiological significance of the major brain metabolites that can be measured using clinical MRS systems. These metabolites include N-acetylaspartate(NAA), creatine, choline-containing compounds, myo-inositol, glutamate and glutamine, lactate, and gamma-amino butyric acid (GABA). For the major adult neuropsychiatric disorders (schizophrenia, bipolar disorder, major depression, and the anxiety disorders), we highlight the most consistent MRS findings, with an emphasis on those with potential clinical or translational significance. Reduced NAA in specific brain regions in schizophrenia, bipolar disorder, post-traumatic stress disorder, and obsessive–compulsive disorder corroborate findings of reduced brain volumes in the same regions. Future MRS studies may help determine the extent to which the neuronal dysfunction suggested by these findings is reversible in these disorders. Elevated glutamate and glutamine (Glx) in patients with bipolar disorder and reduced Glx in patients with unipolar major depression support models of increased and decreased glutamatergic function, respectively, in those conditions. Reduced phosphomonoesters and intracellular pH in bipolar disorder and elevated dynamic lactate responses in panic disorder are consistent with metabolic models of pathogenesis in those disorders. Preliminary findings of an increased glutamine/glutamate ratio and decreased GABA in patients with schizophrenia are consistent with a model of NMDA hypofunction in that disorder. As MRS methods continue to improve, future studies may further advance our understanding of the natural history of psychiatric illnesses, improve our ability to test translational models of pathogenesis, clarify therapeutic mechanisms of action,and allow clinical monitoring of the effects of interventions on brain metabolicmarkers

Activation of left posterior cingulate gyrus by the auditory presentation ofthreat-related words: an fMRI study

This study investigated the cortical response to hearing threat-related and neutral words using functional magnetic resonance imaging (fMRI) in 16 coronal planes. Right-handed volunteers listened to (i) neutral words alternating with no words as the control condition, and (ii) neutral words alternating with threat-related words as the experimental condition. Threat-related words compared to neutral words activated left posterior cingulate gyrus in eight of 10 subjects with activation most prominent in the retrosplenial region. Patterns of activation produced by neutral words compared to no words included bilateral temporal and frontal regions but not posterior cingulate. The retrosplenial cingulate region has recently been implicated in episodic memory processes. We discuss the possible role of the posterior cingulate cortex in processes involving emotion and memory and in anxiety disorders.

HYPERVENTILATION-INDUCED PANIC ATTACKS IN PANIC DISORDER WITH AGORAPHOBIA

Eight minutes of hyperventilation to an end-tidal PCO2 of less than 20 mmHg led to a panic attack in 7 of 12 patients with panic disorder with agoraphobia and only 1 of 12 normal controls. Patients experienced greater increases in panic symptoms than controls during hyperventilation. Patients who reported more distress from somatic symptoms of hyperventilation during the preceding week were more likely to panic during hyperventilation. Patients who panicked during hyperventilation exhibited a delayed recovery of normocapnia following hyperventilation. Hyperventilation by this protocol is an effective means of inducing panic attacks in the laboratory. A hyperventilation challenge may identify a subgroup of patients for whom hyperventilation symptoms are frequently associated with panic.

Lactate infusions and panic attacks: Do patients and controls respond differently?

Ten patients with panic disorder or agoraphobia with panic attacks and 10 normal controls received infusions of normal saline (placebo) and sodium lactate in a single-blind design. The time course of changes in the dependent variables was closely monitored, and expectancy biases and demand characteristics were minimized. Lactate increased self-reported anxiety and heart rate equally in patients and controls. The only variables showing statistically different responses between the groups were systolic and diastolic blood pressure. Overall, in both groups, the effects of lactate were quite similar to states of natural panic or anxiety for both self-report measures and heart rate. Patients had a tendency to endorse somatic symptoms indiscriminately. Our data do not support response to lactate as a biological marker of proneness to panic attacks.

Panic Disorder and Chest Pain in the Coronary Care Unit

Consecutive admissions to a university hospital coronary intensive care unit were prospectively evaluated using a modified version of the Structured Clinical Interview for DSM-III-R by interviewers blind to the patients cardiac status. Panic disorder was present in almost one-third of the patients. Four (21%) of the 19 patients with panic disorder also had positive cardiac findings, including 2 who had myocardial infarctions. Of the 27 patients with negative cardiac findings, 15 (55.5%) had panic disorder. Whereas panic disorder and coronary heart disease may coexist in patients with acute chest pain, there appears to be a very high prevalence of panic disorder among patients in whom cardiac disease has been excluded.

Separating subjective emotion from the perception of emotion-inducing stimuli: An fMRI study

fMRI was used to dissociate neural responses temporally associated with the subjective experience of emotion from those associated with the perception of emotion-inducing stimuli in order to better define the emotion-related functions of the amygdala, lateral orbital frontal cortex (OFC), and hippocampus. Subjects viewed aversive pictures followed by an extended post-stimulus period of sustained subjective emotion. Brain regions showing activation paralleling the period of sustained subjective emotion were distinguished from those showing activation limited to the period of aversive picture presentation. Behavioral results showed that subjective ratings of emotion remained elevated for 20 s after offset of the aversive pictures. fMRI results showed that viewing aversive pictures activated the amygdala, lateral OFC, and hippocampus. Subjective emotion (present both during and after aversive pictures) was temporally associated with activation in the right lateral OFC and left hippocampus but not the amygdala. Ratings of subjective emotion were correlated with activation in the right lateral OFC and left hippocampus. The results support direct amygdala involvement in emotion perception but suggest that amygdala activation is not temporally associated with subjective emotion that occurs after the offset of emotion-related stimuli. The results are consistent with a general role for the lateral OFC in monitoring or reflecting on internal experience and show that hippocampal activation is sustained during a period of subjective emotion, possibly related to enhanced memory encoding for the aversive pictures.