Table 2.
How do current in vivo neuroimaging studies fare in detecting adult human hippocampal neurogenesis?
| Criterion | Our assessment | Evidence |
|---|---|---|
| Strength of association (A strong association is likely to have a more causal basis than a weak association.) | Moderate/strong | Many longitudinal studies demonstrate significant effects of active interventions that are known to promote adult animal neurogenesis on human hippocampal neuroimaging phenotypes. Studies of the effects of exercise on hippocampal volume report medium-to-large effect sizes in a cohort of healthy and schizophrenia subjects (η2 =0.85)72 and elderly subjects (left: partial η2 =0.06, right: partial η2 =0.07).84 An investigation of the effect of exercise on CBV found a large effect size specifically within the dentate gyrus (we estimated a Cohen’s d =1.2 based on graphical representations of means and standard deviations).73 Also, learning is associated with a large effect specifically on hippocampal volume (estimated d =1.25 based on t-values and degrees of freedom).69 The effects of a variety of treatments for mood disorders on hippocampal volumes are also associated with medium-to-large effect sizes, for example, various antidepressants (left: d =0.48, right: d =0.27);93 paroxetine (left: d =0.44, right: d =0.31);94 lithium (left: d =0.24 for first follow-up and 0.3 for second follow-up, right: d =0.2 for first follow-up and 0.26 for second follow-up);101 and electroconvulsive therapy (left: r =0.98, right: r =0.97).71 |
| Consistency (There are similar reports of associations between adult neurogenesis and imaging outcomes across populations, methods, interventions and investigators.) | Strong | Interventions that enhance adult hippocampal neurogenesis in animal models (for example, exercise, antidepressants, and learning) increase hippocampal volumes, and CBV, BOLD-fMRI and MRS signals in the hippocampus across healthy and diseased, young and aged populations.68–73,75,84,90–94,101 Conversely, physiological processes that reduces adult hippocampal neurogenesis in animal models (for example, stress and aging) have the opposite effect on dentate gyrus and hippocampal phenotypes across a spectrum of imaging modalities.74,76–79,105–106,108,114–122 |
| Specificity (Changes in adult neurogenesis specifically influences the outcome of the neuroimaging measure.) | Weak/moderate | This criterion is difficult to assess as current in vivo imaging does not afford cellular resolution. However, there is some indirect evidence for specific effects on hippocampal neurogenesis. For example, learning and exercise lead to increases in the volume of the hippocampus but not of other brain regions examined, for example, thalamus and caudate nucleus.69,84 Also, within the hippocampus, exercise specifically increases CBV of the dentate gyrus but not of other hippocampal subregions.73 Aging is associated with a weaker dentate gyrus/CA3 BOLD-fMRI signal that is linked to poorer memory performance in a pattern separation task.78 There has been one report of a neural progenitor-specific metabolite marker; this finding requires replication.122 |
| Temporality (Changes in adult neurogenesis over time leads to changes in neuroimaging outcome measures on the same timescale.) | Moderate | Prospective randomized controlled trials at three time points have shown that learning and exercise produce continuous increases in the volume of hippocampus (over a period of 6 months to 1 year).69,84 However this criterion is difficult to assess as the precise time course of the adult human neurogenesis is not known. |
| Biological gradient (Neuroimaging outcome measures increase/decrease monotonically with increases/decreases in adult neurogenesis.) | Weak/moderate | Prospective aging studies show that the hippocampus decreases in volume to a greater extent than other brain regions over time.114–117 However, studies involving active interventions such as exercise usually include only one level of the intervention due to sample size, time and cost efficiency limitations. Also, methodological variation across studies limits their comparability; for example, it is difficult to quantify the extent of learning and stress across subjects in different studies. Also, the types and dosage of antidepressants vary among patients. |
| Plausibility (The observed changes in neuroimaging outcomes can be rationally explained by changes in adult neurogenesis.) | Moderate | It is logical to predict that changes in adult neurogenesis on a microscopic level influence widespread function of the dentate gyrus, which may be observable on a macroscopic level. The addition of new granule cells, with their unique firing patterns and heightened synaptic plasticity, is likely to lead to extensive remodeling of dentate gyrus connections and may conceivably affect intra- and inter-hippocampal functional connectivity.155,163 It is also plausible that vascular growth and glia activation are required to support the development and integration of newborn granule cells in the existing circuit and hence lead to larger-scale alterations of hippocampal responses over time. It remains unclear whether observable macroscopic structural changes (measured using today’s scanners) can be solely produced by changes in the sparse population of adult-born neurons, particularly as macroscopic changes may also result from neurogenesis-independent glia or growth factor-related mechanisms. |
| Experimental manipulation (An association between adult neurogenesis and an imaging measure that is specifically produced by an intervention in a controlled setting is more convincing than an observational study.) | Moderate/strong | Parallel human-animal model studies show that the exercise- induced increase in adult neurogenesis correlates with in vivo dentate gyrus CBV signal within the same study animals.73 Electroconvulsive shock-induced increase in progenitor cell proliferation correlates with increases in a metabolite marker of neural progenitor cells in vitro and in vivo.122 Age-related declines in adult neurogenesis, MRI-measureable hippocampal volume and hippocampus-dependent memory tasks were observed in in vivo and postmortem studies of the same study rodents.111 |
Abbreviations: BOLD-fMRI, blood-oxygenation-level-dependent functional magnetic resonance imaging; CBV, cerebral blood volume; MRS, magnetic resonance spectroscopy.
We assess the strength of the evidence based on Bradford Hill’s criteria for causation.166,167 We argue that although there is still much room for improvement in terms of study design and data interpretation, studies using currently available neuroimaging methods have the capacity to establish links between adult neurogenesis and macroscopic changes in the human hippocampus, as well as changes in cognition and affect. Future studies can benefit from the use of multimodal imaging, which will mitigate the inherent weaknesses found in individual methods. By cross-validating results across laboratories, where data acquisition and analyses are performed differently across different subject populations, the consistency and totality of evidence can be strengthened. Prospective studies with multiple time points (for example, in aging populations or those who receive antidepressant medications or exercise) will enhance both the reliability and biological plausibility of the findings. Longitudinal studies that establish a dose–response relationship or other biological gradient, for example, increasing levels of an active intervention such as physical activity, antidepressants and stress that correlate with changes in hippocampal structure, function and connectivity, will also enhance the validity of the neuroimaging measure. Finally, conducting the same prospective studies side-by-side with animal models in which adult neurogenesis can be precisely manipulated will substantiate in vivo neuroimaging markers as valid measures of adult neurogenesis.