Introduction
Craniopharyngioma (CP) is a rare, benign, embryonic pituitary tumor with an aggressive growth pattern and high recurrence rate, associated with increased mortality and morbidity in cardiovascular disease [
1‐
6]. Adults with childhood CP, especially patients with hypothalamic involvement, are also at risk of cognitive impairment with deficits in memory, attention, and processing speed, even on complete hormone replacement therapy [
7]. These deficits are thought to be due to both the tumor itself and its treatment, including surgical removal and additional cranial radiotherapy (CRT), leading to hypothalamic injury [
8]. It has been hypothesized that the focal hypothalamic lesion induces changes in hypothalamic networks through the processes of diaschisis, i.e., altered function of an neuroanatomical structure due to damage in another remotely connected structure, and/or transneuronal degeneration, i.e., neuronal degeneration due to damage of nearby neurons, which may also contribute to the cognitive impairment in these individuals [
9].
A previous study using magnetic resonance imaging (MRI) voxel-based morphometry have demonstrated reduced gray and white matter volumes in the limbic areas connected to the hypothalamus and an association between impaired long-term memory and reduced gray matter volumes in the posterior cingulate cortex in adolescents with childhood CP [
10]. Another previous study using diffusion tensor imaging (DTI), reported an association between microstructural white matter alterations in the dorsal cingulum and a decline in episodic visual memory, visuospatial abilities, executive function, attention, and processing speed in adults with childhood CP [
11]. Further, this study also reported an association between alterations in the ventral cingulum and a decline in episodic visual memory, and an association between alterations in the uncinate fasciculus and a decline in semantic memory [
11].
Blood-oxygen level dependent functional MRI (fMRI) is based on the magnetic susceptibility of blood. Alterations in the MRI signal arise due to local changes in blood oxygenation, flow, and volume from the metabolism associated with neuronal activity. Neuroimaging studies on CP patients are scarce and, to our knowledge, only two previous studies have used fMRI to investigate functional brain alterations in relation to cognitive function in childhood CP patients [
12,
13]. However, both studies had relatively small sample sizes and the follow-up time after treatment was relatively short.
The multi-source interference task (MSIT) can be used to test cognitive interference processing, which is the ability to be attentive to goal-relevant information and at the same to be able to reject goal-irrelevant information. This has been shown to reliably activate the cingulo-fronto-parietal (CFP) attention network, which includes the dorsal anterior cingulate cortex, the dorsal anterior midcingulate cortex, and the dorsolateral prefrontal cortex that is involved in target detection, novelty detection, error detection, decision-making, response selection, and stimulus/response competition [
14,
15]. These regions are all partially connected through the white matter tracts previously investigated in CP patients [
11].
Our aim was to use the MSIT during fMRI to assess cognitive interference processing in terms of behavioral performance and fMRI activity in adults with childhood CP. In addition, we wanted to investigate whether hypothalamic injury had any impact on this. We hypothesized that CP patients would exhibit longer response times, lower accuracy performance, and altered fMRI activity in the CFP attention network compared to controls. Furthermore, we suspected that these differences would be more pronounced in patients with hypothalamic injury.
Discussion
The aim of this study was to assess cognitive interference processing in adults with childhood CP with the MSIT during fMRI acquisition in terms of behavioral performance and fMRI activity. Our results show that there was a difference in both reaction time and accuracy performance between the interference and control tasks for both the CP patients and controls, which confirms the validity of the method. However, there were no differences in reaction time, accuracy performance, or fMRI activity between any of the groups in performing the interference tasks.
A significant difference in reaction time as well as in accuracy performance was recorded between the more cognitively demanding interference tasks and the control tasks, for both the CP patients, the subgroups of CP patients with and without hypothalamic injury, respectively, and the controls. This indicate that the MSIT was performed according to instructions described in the literature [
14,
15]. Nevertheless, there were no differences in neither reaction time nor accuracy performance between any of the investigated groups. The interference effect, i.e., the difference in reaction time and accuracy performance between the interference and control tasks, also did not differ between any of the investigated groups.
The interference effect was additionally studied regarding fMRI activity and revealed activation in the CFP attention network as expected in both groups, suggesting that the results are reliable. Notably, the difference in fMRI activity that was needed to solve more cognitively demanding interference tasks compared to the control tasks did not differ between any of the investigated groups. This suggests that the CP patients performed cognitive interference processing on a comparable level to controls, without any compensatory activation in the CFP attention network.
The MSIT has previously been used to study alterations in behavioral performance and fMRI activation in different conditions, commonly within the field of psychiatry [
28‐
32], but also in patients with heart disease [
33]. The results are highly varying and only some studies acquired fMRI data during the MSIT whereas most studies have only presented results on behavioral performance. In previous studies using fMRI, decreased fMRI activity in the rostral anterior cingulate/medial prefrontal cortex and the precuneus/posterior cingulate cortex have been seen in patients with schizophrenia and increased fMRI activity in the medial frontal cortex in patients with obsessive-compulsive disorder but no differences in behavioral performance compared to controls [
28,
29]. These somewhat ambiguous results could be due to different conditions affecting different parts of the brain and that structures within the investigated area are responsible for different functions. In other words, increased activity in one area could result in the same altered behavioral performance as decreased activity in another area.
Neuroimaging studies on childhood CP are scarce and comparisons of the results are difficult to interpret, largely due to methodological variations and limitations such as small samples, different treatment protocols, and different follow-up times (Table
3). A few previous studies have demonstrated that white matter integrity in the investigated areas correlated negatively to given radiation dose, reduced gray and white matter volumes in the limbic areas, and have shown a negative correlation between long-term memory and gray matter in the posterior cingulate cortex [
10,
34]. In another previous study, using a subset of patients included in the present study, microstructural white matter integrity was assessed using DTI and tractography and an association between decreased integrity in the dorsal cingulum and a decline in episodic visual memory, visuospatial abilities, executive function, attention, and processing speed was found [
11]. Furthermore, the same study found an association between decreased integrity in the ventral cingulum and a decline in episodic visual memory, and an association between decreased integrity in the uncinate fasciculus and a decline in semantic memory in adult childhood CP patients [
11].
Table 3
Previous neuroimaging studies on craniopharyngioma patients
| 4 | 13–17 years | >1 | Surgery CRT | fMRI to evaluate activity in correlation to visual food cues at 3 T | Increased activity in medial OFC following meal |
| 10 | Median 17.8 | >4 | Surgery CRT | fMRI test for emotional face recognition at 1.5 T | Altered activity in PFC during memory retrieval |
| 51 | Median 9.2 (range 2.1–19.3) | 3 | Surgery CRT (proton radiation equivalent to 54 Gy) | Atlas-based ROI analysis of DTI at 1.5 T | Negative association between WM integrity and radiotherapy |
| 11 | 17.4 (IQR 8.6–26.2) | ~ 5–10 | Surgery | Voxel-based morphometry at 1.5 T | Reduction of GM and WM volumes in limbic areas |
Fjalldal et al., 2018 [ 11] | 41 | ≥17 | Median 35 (range 17–56) | Surgery CRT (50 [range 35–55] Gy) | DTI and tractography at 3 T | Negative association between WM integrity in the cingulum and cognitive functions |
Only two previous studies have used fMRI to study cognitive impairment in childhood CP patients. These studies demonstrated lower fMRI activity during the premeal test and higher fMRI activity during the post-meal test as compared to controls [
12], and differential recruitment of fronto-limbic brain regions during emotional face recognition [
13]. Even though the hypothalamus is partially connected to the limbic system as well as partially to the CFP attention network, investigated in the present study, the investigated cognitive domains, chosen for evaluation, differs between the studies and hence comparisons of the results to the present study are not easily interpreted [
35,
36].
In comparison to previous studies on CP survivors that have demonstrated cognitive deficits, and functional and structural brain alterations, albeit using slightly different techniques and testing slightly different cognitive domains and neuroanatomical structures [
7‐
13], the results of the present study may appear somewhat contradictory. However, not all previously investigated cognitive domains and/or neuroanatomical structures were affected. For example, one study using a sub-sample of the same CP patient group as in the present study found cognitive deficits in semantic, episodic, and visual memory, but no deficits in working memory, executive function, attention or processing speed [
11]. In this context, the results of the present study may not be that surprising since cognitive interference processing is more related to executive function and attention than to semantic, episodic, and visual memory because it tests the ability to select and organize relevant information and to suppress irrelevant information. The present results are also interesting because the CFP attention network, situated in an area where microstructural alterations in major white matter tracts have previously been reported [
11], have never been investigated in CP survivors before. Thus, the results of the present study should therefore rather be considered as another piece of information required to better characterize this condition.
To our knowledge, this is the first study that has used the MSIT in combination with fMRI to study cognitive interference processing in adults with childhood CP. Reaction times, accuracy performance, and fMRI activity indicate that the MSIT was performed correctly and that the results are reliable. Still, there are some limitations to this study. Firstly, the study groups were, due to the rareness of the disease and the long follow-up time, relatively small and may have underpowered the study, leading to discarded true differences between the investigated groups. Secondly, a possible selection bias might have occurred when subjects that were unable to perform the task were excluded.
In conclusion, adults with childhood CP performed cognitive interference processing equally well as controls in terms of response times and accuracy performance and did not exhibit altered fMRI activity in the CFP attention network during the process. This was also true for the two subgroups with and without hypothalamic injury. However, this does not exclude deficits in other cognitive domains or alterations in other functional networks. Further studies are needed to map what cognitive domains and functional networks are affected/unaffected in CP survivors in order to better characterize the condition and to optimize treatment and support for these individuals.
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