Basal Ganglia Hypermetabolism and Symptoms of Fatigue during Interferon-α Therapy (2007), Capuron et al.

[jnmaciuch]

Basal Ganglia Hypermetabolism and Symptoms of Fatigue during Interferon-α Therapy (2007)​

Lucile Capuron, Giuseppe Pagnoni, Marina F Demetrashvili, David H Lawson, Fiona B Fornwalt, Bobbi Woolwine, Gregory S Berns, Charles B Nemeroff & Andrew H Miller

Interferon (IFN)-α is a cytokine of the innate immune response that is well known for inducing behavioral alterations and has been used to study effects of cytokines on the nervous system. Limited data, however, are available on the sites of action of IFN-α within the brain and their relationship with specific IFN-α-induced symptoms.

Using a longitudinal design, whole-brain metabolic activity as assessed by fluorine-18-labeled fluorodeoxyglucose uptake and positron emission tomography was examined before and 4 weeks after IFN-α administration in patients with malignant melanoma. Changes in metabolic activity in relevant brain regions were then correlated with IFN-α-induced behavioral changes. IFN-α administration was associated with widespread bilateral increases in glucose metabolism in subcortical regions including the basal ganglia and cerebellum. Decreases in dorsal prefrontal cortex glucose metabolism were also observed.

Prominent IFN-α-induced behavioral changes included lassitude, inability to feel, and fatigue. Correlational analyses revealed that self-reported fatigue (specifically as assessed by the ‘energy’ subscale of the Visual Analog Scale of Fatigue) was associated with increased glucose metabolism in the left nucleus accumbens and putamen. These data indicate that IFN-α as well as other cytokines of the innate immune response may target basal ganglia nuclei, thereby contributing to fatigue-related symptoms in medically ill patients.

[Breaks added]

Link | PDF

 

[jnmaciuch]

And old study but one that struck me as interesting. It suggests that IV administration of interferon alpha is capable of creating domain-specific effects associated with neural metabolism. [Edit: this analysis does not show that the effect of IFN-a on these brain regions is caustative--just that the magnitude of those brain metabolism changes correlates with degree of reported fatigue]

[Edit: I'll also note there was no placebo group and therefore no blinding]

Subjects​

Using a longitudinal design, two PET scans (before and after 4 weeks of IFN-α therapy) were performed in a total of 12 right-handed patients [nine men, three women, mean age 49 (SD 9) years] diagnosed with stage II–IV malignant melanoma with a 50% or greater risk of recurrence. All patients had been surgically rendered clinically free of disease and were eligible to receive high-dose IFN-α therapy. Patients were recruited from the Winship Cancer Institute at Emory University. Medical exclusion criteria included diabetes; unstable cardiovascular, endocrine, hematological, hepatic, or renal disease; brain damage and/or neoplastic involvement; neurological disease; and severe or uncontrolled visual disturbances. Patients with a diagnosis of schizophrenia, bipolar disorder, or current major depression as determined by Structured Clinical Interview for DSM-IV Axis I disorders (Association, 1994); a Mini Mental State Exam ⩽24 (Folstein et al, 1983); or active treatment with antipsychotics, antidepressants, or benzodiazepines were also excluded. All patients were offered antidepressant treatment to prevent depression during IFN-α administration, and all declined. IFN-α2b (IntronA, Schering-Plough) was administered intravenously at a dose of 20 million units per square meter of body-surface area 5 days/week for 4 weeks. Concomitant medications for fever and nausea due to IFN-α administration were allowed during the study, but psychotropic medications, including antipsychotics, antidepressants, and benzodiazepines, were not.

Behavioral Assessments​

Behavioral assessments were performed at baseline (before the initiation of IFN-α therapy) and after 4 weeks of IFN-α treatment. Assessments included the observer-rated MADRS (Montgomery and Asberg, 1979), a 10-item scale assessing the severity of depressive symptoms, including sadness, inner tension, concentration difficulties, inability to feel (defined as reduced interest in surroundings and usually pleasurable activities and/or reduced emotional responsivity), pessimistic thoughts, suicidal thoughts, reduced sleep, reduced appetite, and lassitude (defined as difficulty getting started or slowness initiating and performing everyday activities). Based on previous work indicating that fatigue is the most prominent IFN-α-induced symptom (Capuron et al, 2002a), subjects were also administered the self-report VAS-F, an 18-item 100-mm visual analogue scale, which assesses fatigue using two series of inverse items: a ‘fatigue’ series (13 items including ‘tired’, ‘sleepy’, ‘drowsy’, ‘fatigued’, ‘worn out’, ‘bushed’, ‘exhausted’, difficulty ‘keeping eyes open’, difficulty ‘moving my body’, difficulty ‘concentrating’, difficulty ‘carrying on a conversation’, ‘desire to close my eyes’, ‘desire to lie down’) and an ‘energy’ series (five items including ‘energetic’, ‘active’, ‘vigorous’, ‘efficient’, ‘lively’), which together represent ‘fatigue’ and ‘energy’ subscales (Lee et al, 1991). The VAS-F has been shown to possess good overall psychometric properties (Lee et al, 1991; Meek et al, 2000; Miaskowski and Lee, 1999), although in a comparison of multiple fatigue instruments and their subscales (see below), the energy subscale of the VAS-F was found to exhibit the highest reliability in measuring fatigue-related symptoms in cancer patients (Meek et al, 2000).

 

[jnmaciuch]

Also I'd never heard the word "lassitude" before but wow does it cover a lot of my experience. If only it wasn't so closely tied in connotation to depression. One thing I'm skeptical of is the measure of "inability to feel". The values change from 0.17 (−0.08 to 0.41) at baseline to 1.42 (0.63–2.20) post-treatment.

This is how the question assessing it is phrased:

8. Inability to feel
Representing the subjective experience of reduced interest in the surroundings, or activities that normally give pleasure. The ability to react with adequate emotion to circumstances or people is reduced.
0 Normal interest in the surroundings and in other people.
1
2 Reduced ability to enjoy usual interests.
3
4 Loss of interest in the surroundings. Loss of feelings for friends and acquaintances.
5
6 The experience of being emotionally paralysed, inability to feel anger, grief or pleasure and a complete or even painful failure to feel for close relatives and friends

From Montgomery et al. (1979) (scihub link here)

So mean score of 1.42 would mean that, at most, the participants were reporting reduced ability to enjoy usual interests, not severe emotional impairment. Just as you might expect from someone experiencing simply debilitating fatigue and reduced capacity for activity, rather than someone experiencing an emotional state akin to clinical depression