  Purpose: Most MR spectroscopy (MRS) pulse sequences rely on broadband
excitation with water saturation and typically focus on upfield signals. By
contrast, the downfield spectrum, which contains many potentially useful
resonances, is typically not targeted because conventional water-suppressed
techniques indirectly saturate the labile protons through exchange.
Relaxation-enhanced MRS (RE-MRS) uses frequency-selective excitation while
actively avoiding bulk water perturbation, thereby enabling high-quality
downfield spectroscopy. However, RE-MRS typically requires very long (typically
>40 ms) echo times (TEs) due to its localization module, which inevitably
decreases sensitivity and filters shorter T2 components. Here, we overcome this
limitation by combining RE-MRS and image selected in vivo spectroscopy (ISIS)
localization, abbreviated iRE-MRS, which in turn allows very short TEs (5 ms
using our hardware).
  Methods: Experiments were performed in vitro for validation as well as and in
in vivo rat brains at 9.4T.
  Results: The new iRE-MRS methodology was validated in phantoms where good
performance was noted. When the downfield spectrum was investigated at short
TEs in in vivo rat brains, iRE-MRS provided very high sensitivity; the ensuing
downfield spectra encompassed numerous broad peaks, as well as a broad
baseline. All downfield spectral peaks were highly attenuated by increasing TEs
as well as by applying water saturation, although to different extent. The
signal ratios also varied between TEs, suggesting that exchange rates are
different among the downfield signals.
  Conclusions: Short-TE iRE 1H downfield MRS opens new directions in the
investigation of in vivo downfield metabolites and their role on healthy and
disease processes.
